Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 20, 2026.

The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections

Karlijn B. Rombouts, Tara A. R. van Merrienboer, Johannes C. F. Ket and 3 more

European Journal of Clinical Investigation · 2021 · Review · CC BY

doi:10.1111/eci.13697

Abstract

Background. Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case of rupture. In addition to dilation, the aortic layers can separate by a tear within the layers, defined as aortic dissections (AD). Vascular smooth muscle cells (vSMC) are the predominant cell type within the aortic wall and dysregulation of vSMC functions contributes to AA and AD development and progression. However, since the exact underlying mechanism is poorly understood, finding potential therapeutic targets for AA and AD is challenging and surgery remains the only treatment option.

Methods. In this review, we summarize current knowledge about vSMC functions within the aortic wall and give an overview of how vSMC functions are altered in AA and AD pathogenesis, organized per anatomical location (abdominal or thoracic aorta).

Results. Important functions of vSMC in healthy or diseased conditions are apoptosis, phenotypic switch, extracellular matrix regeneration and degradation, proliferation and contractility. Stressors within the aortic wall, including inflammatory cell infiltration and (epi)genetic changes, modulate vSMC functions and cause disturbance of processes within vSMC, such as changes in TGF‐β signalling and regulatory RNA expression.

Conclusion. This review underscores a central role of vSMC dysfunction in abdominal and thoracic AA and AD development and progression. Further research focused on vSMC dysfunction in the aortic wall is necessary to find potential targets for noninvasive AA and AD treatment options.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Aortic aneurysms (AA) are defined as a progressive weakening of the aortic wall, leading to gradual dilatation. Based on their anatomical location, AA are classified into thoracic aorta aneurysms (TAA) and abdominal aortic aneurysms (AAA), or thoraco‐abdominal AA (Crawford classification) when affecting both locations. Both TAA and AAA share some common pathophysiological characteristics and risk factors, including ageing, male sex and smoking., Moreover, TAA is caused by inherited gene mutations in approximately 20% of the patients. In addition to the dilation of the aorta, patients may present with aortic dissections (AD). AD are defined as a tear within the intimal layer of the aorta, causing separation of the intimal and medial layers of the aortic wall. AD are divided into Stanford type A (involving the aortic arch) and type B (aortic disease starts after the left subclavian artery). The aorta of AD patients can likely dilate and develop into AA.

The majority of AA patients is diagnosed accidently or after sudden rupture of the aortic wall. Sudden AA rupture is associated with an overall high mortality of 90% due to internal bleeding complications. AD are usually diagnosed acutely; commonly patients report an acute pain between the shoulders. Currently, surgical open or endovascular repair is offered to AA and AD patients with known risk of complications or rupture, mainly based on aneurysm size. Patients are usually also treated with medications for overall cardiovascular risk management. However, the majority of patients with acute type B AD is usually non‐responsive to pharmacological therapy. No further pharmaceutical treatment for prevention, stabilization or reversal of AA and AD is available, since the knowledge about the pathophysiology of aortic wall weakening is limited.

Aortic wall weakening is characterized by loss of vascular smooth muscle cells (vSMCs) due to apoptosis and extracellular matrix (ECM) degradation within the middle layer of the aortic wall. Vascular SMCs are the predominant cell type in the middle aortic layer, called the tunica media. Their embryonic origin is dependent on the location in the aortic wall; in the ascending aorta and the aortic arch, vSMCs are neural crest‐derived, whereas in the descending aortic vSMC originate from somatic mesoderm. vSMCs are paramount for providing structural and functional integrity of the aortic wall and ECM synthesis. They can adapt to environmental stimuli and mechanical stress due to their characteristic vSMC plasticity ‐ being able to switch between a contractile and a synthetic phenotype.

Imbalance in vSMC phenotypic switching can contribute to several pathological processes causing cardiovascular diseases, including AA and AD. However, the exact role of vSMC dysregulation in AA and AD development and progression is complex and poorly understood. In this review, we summarize current knowledge on vSMC functions in the aortic wall and describe the potential role of vSMC dysfunction in abdominal and thoracic AA and AD development and progression. Knowledge on vSMC‐mediated pathomechanisms underlying early and advanced stages of aortic wall weakening will aid in the design of nonsurgical treatments for prevention and stabilization of AA and AD. Figure 1 gives an overview of the described vSMC functions, stressors and disturbed processes involved in progressive aortic wall weakening. A systematic database search was performed to select articles for this review and the screening process is depicted in Figure S1.

Apoptosis of vSMC

The loss of vSMC in the medial layer of the aortic wall due to apoptosis is an early hallmark of AA development. Decreased vSMC density weakens the aortic wall and limits matrix repair capacity, since vSMCs are essential for ECM regeneration. The decrease in vSMC density and coincident reduction in ECM regeneration make the aortic wall more prone to dilatation and thereby contribute to development and progression of AA and AD. A decrease in vSMC number in AAA compared with healthy human aortic tissue was first demonstrated by López‐Candales et al. High levels of p53 (cell cycle arrest and apoptosis marker) observed in AAA tissue suggested that this decreased vSMC density was caused by vSMC apoptosis. Increased vSMC apoptosis in AAA tissue was described in multiple human,,, and rodent studies. Various mechanisms to induce the switch of vSMC to a more senescent phenotype with high susceptibility to apoptosis were reported and are shown in Figure 2. Inflammatory cell infiltration into the human aneurysmal aortic wall contributes to vSMC programmed cell death by production of apoptosis‐promoting molecules, such as cytokines and perforin., An important cytokine involved in the inflammatory response in the aneurysmal aortic wall is monocyte chemoattractant protein‐1 (MCP‐1), and elevated MCP‐1 levels increased vSMC apoptosis in different AAA mouse models.,,, Oxidative stress, caused by products such as nitric oxide and oxygen‐free radicals produced by atherosclerotic plaques on the inside of the aortic wall and by vSMC, induces vSMC apoptosis in rats. Also, endoplasmic reticulum (ER) stress is demonstrated in human AAA tissue and accompanied by severe vSMC apoptosis.

In the human thoracic aorta, the infiltration of inflammatory cells and ER stress induced by mechanical wall stress are associated with vSMC apoptosis, contributing to TAA and thoracic aortic dissection (TAD) development and progression., vSMC isolated from human TAA tissue exposed to oxidative stress demonstrate pro‐apoptotic traits, such as DNA fragmentation, cellular shrinkage, membrane blebbing and chromatin condensation, indicating that oxidative stress contributes to vSMC apoptosis activation in the thoracic aorta., vSMC apoptosis in human TAA and TAD tissue is regulated by an imbalance between pro‐apoptotic Bcl‐2‐associated X protein (BAX) and anti‐apoptotic B‐cell lymphoma 2 (BCL2) levels. Mechanical stress induced downregulation of transcriptional regulator yes‐associated protein‐1 (YAP‐1) in human thoracic aortic aneurysm and dissection (TAAD) tissue and was associated with increased vSMC apoptosis. In contrast, upregulation of YAP‐1 in a rat model has a protective effect against TAD formation by decreasing vSMC apoptosis. Heat‐shock protein (HSP)70 and HSP27, which are increased in response to cellular oxidative stress in human TAA and TAD tissue respectively, also both have an anti‐apoptotic and protective effect in the thoracic aortic wall.

Apoptosis can be inhibited by transcription factor EB (TFEB), a master regulator of autophagy. However, TFEB is found to be downregulated in both human and mouse AA lesions, thereby increasing vSMC apoptosis and promoting AAA formation in different mouse models. This critical role for autophagy in regulating vSMC death is also regulated by the autophagy protein 5 gene (ATG5). Deletion of this gene causes loss of autophagy in vSMC and increases susceptibility of vSMC death and enhancement of ER stress‐dependent inflammation within the aortic wall.

Phenotypic switch of vSMC

Vascular smooth muscle cells have the ability to switch from a contractile to a synthetic phenotype in the healthy aortic wall. Synthetic vSMCs are proliferative, while contractile vSMCs are more differentiated and express a higher number of SMC specific contractile markers. During AA and AD progression, the balance between contractile and synthetic vSMC is shifted towards synthetic vSMC and increased proteolytic enzyme production by those vSMC. These proteolytic enzymes can degrade the ECM, which facilitates the detachment of vSMC from the ECM and promotes vSMC migration and apoptosis. vSMC phenotypic switching is reported in AAA,,,,,,,,,,,,,,,,,, TAA,,,,,,,,,, and TAAD,,,,,,, human and rodent studies. An overview of the most important changes and inducers of vSMC phenotypic switching is indicated in Figure 3. The switch is characterized by a reduction in vSMC‐specific contractile proteins, such as smooth muscle 22alpha (SM22alpha) and alpha smooth muscle actin (αSMA) in both thoracic and abdominal aneurysmal aortic tissues.,,,

vSMC phenotypic switching in the abdominal aorta was found to be initiated by inflammatory cell infiltration regulated by MCP‐1 in vitro and in a mouse model. Upregulation of osteoprotegerin (member of the cytokine receptor of tumour necrosis factor (TNF) receptor superfamily) in human AAA biopsies promoted an inflammatory vSMC phenotype with impaired proliferation and increased apoptosis., Oxidative stress is another driver for the switch from contractile to synthetic phenotype., Furthermore, the Notch1 pathway is known to be involved in AAA formation and vSMC‐specific haploinsufficiency of Notch1 maintains the contractile vSMC phenotype and prevents matrix remodelling in the murine abdominal aorta.

In the thoracic aneurysmal aorta, smooth muscle myosin heavy chain 2 (SM‐MHC‐2), smoothelin, calponin and vimentin were also found to be reduced.,, In contrast, the expression of osteopontin, a marker for synthetic vSMC, is increased in human ascending TAA and TAD tissue.,, HSP90 is upregulated in response to cellular stress in human TAD tissue and inhibition of HSP90 in a mouse model has a protective effect on TAD formation by suppressing vSMC phenotypic switching. This is in contrast to the protective effect of upregulated HSP27 and HSP70 against vSMC apoptosis, as described above., Hypertension causes vSMC phenotypic switching mediated by reactive oxygen species (ROS) accumulation in the human thoracic aorta, accompanied by increased mechanical wall stress. ECM‐vSMC connection is crucial for maintenance of vSMC phenotype; vSMC‐specific deletion of the ECM fibulin‐4 gene in a mouse model leads to loss of the vSMC contractile phenotype, hyperproliferation and ascending AA formation.,

ECM regeneration and degradation regulated by vSMC

Vascular smooth muscle cells are involved in regulation of the aortic wall elasticity and production of ECM proteins. Together with elastic ECM fibres, such as collagen and elastin, vSMCs form a functional unit vital for maintaining structural and functional integrity. This connection between vSMC and the ECM is essential for regulation of vSMC functions, such as vSMC contractility. However, ECM degradation occurs in aneurysmal tissue, contributing to rupture and dilation of the aortic wall. vSMCs are actively participating in this process through activation and modulation of matrix metalloproteinases (MMP), the A disintegrin and metalloproteinase (ADAM) family, cathepsins and the fibrinolytic pathway. An overview of the role of vSMC in ECM degradation is shown in Figure 4.

Matrix metalloproteinases (MMP) are endopeptidases capable of degrading ECM proteins, resulting in aortic tissue remodelling. Synthesis levels of MMP by vSMC in AAA tissue are found to be increased compared with control aortic tissues in human and rodent studies, especially of MMP‐2,,,,,,,, and MMP‐9.,,,,,, Also, other MMP, namely MMP‐1,,, MMP‐3, MMP‐7, MMP‐12 and MMP‐13, are expressed by vSMC in AAA tissue. An important MMP regulator found in human AAA tissue is the activator of MMP‐2, called membrane type 1 MMP (MT‐1 MMP).,, In TAA and TAD tissue, increased levels of MMP‐1, MMP‐2 and MMP‐9 expression by vSMC compared with control are reported.,,,,, MMP‐2 has a dual role in ECM turnover in the mouse thoracic aorta: it mediates ECM degradation, as well as ECM synthesis. MMP‐17 loss of function in a genetic mouse model resulted in dysfunctional vSMC, altered ECM and increased TAA susceptibility, which suggested that proteolytic MMP‐17 activity is an important regulator of vSMC function. The secretion and activation of MMP is regulated by tissue inhibitors of matrix metalloproteinases (TIMP) expressed in AAA tissue,,,,,, and TAA and TAD tissue.,

The proteolytic function of the ADAM family of metalloproteases regulated by vSMC also plays a role in ECM degradation. Similar expression levels of ADAMs 8, 9, 10, 12, 15 and 17 were found in vSMC of human AAA tissue and control aorta. In contrast, ADAM17 was upregulated in mouse AAA and human TAA tissue, and ADAM17 deficiency in vSMC had a protective function in two different mouse models., In human TAAD tissue, increased expression of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)‐1 and ADAMTS‐4 localized in vSMC was reported compared with control aortic tissue. Increased levels of ADAMTS‐1 and ADAMTS‐4 were associated with more degradation of the ECM proteoglycan versican.

The activation of another type of proteases, called cathepsins, can modulate the ECM and vSMC function in the aortic aneurysmal wall as well. Cathepsins B, D, G, L and S were found, localized in vSMC, in higher concentrations in human AAA tissue, compared with control.,,, Cathepsins can promote vSMC apoptosis,, elastin degradation, protease activity, and inflammatory cell accumulation. Reduced levels of the cysteine protease inhibitor cystatin C were demonstrated in human AAA lesions and complete cystatin C knockout in an AAA mouse model resulted in inflammatory cell accumulation, severe elastin fragmentation and increased vSMC apoptosis.

Extracellular matrix breakdown by proteolytic enzymes and vSMC apoptosis increases arterial wall permeability and thereby the advection of plasma proteins interacting with vSMC and ECM in the aortic wall. As a result, high concentrations of plasminogen are present and activate the fibrinolytic pathway in the aortic wall. In the human abdominal aorta, the expression of tissue‐type plasminogen activator (t‐PA) on vSMC membranes can activate plasminogen into plasmin. Once active, plasmin is involved in MMP activation and fibronectin degradation, both leading to vSMC detachment from the ECM. Overexpression of plasminogen activator inhibitor (PAI‐1), an inhibitor of t‐PA and urokinase plasminogen activator (u‐PA), in an AAA rat model prevented aneurysm formation by the inhibition of plasminogen activators and MMP. In human TAA tissue, accumulation of plasminogen, t‐PA, u‐PA and plasmin was also seen, associated with vSMC. Inhibition and clearance of plasmin in human TAA tissue is regulated by plasmin‐protease nexin 1 (PN‐1) complexes internalized via low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) in vSMC. Overexpression of PN‐1 and PAI‐1 mRNA and proteins in human vSMC cultures isolated from TAA tissue compared with TAD and control tissue was associated with plasmin inhibition and protection of vSMC from detachment and death.

vSMC proliferation

Vascular smooth muscle cells proliferation increases the number of vSMC within the aortic wall and can therefore have a protective effect and delay AA and AD development. However, diminished proliferative capacity is seen in human AAA‐derived vSMC compared with nonaneurysmal vSMC. Inhibition of vSMC proliferation in human AAA biopsies is caused by an G1 cell cycle arrest, regulated by urocortin‐2. High aortic flow causes aortic mechanical stretch, and this stimulates endothelial cell and vSMC proliferation in an experimental rat model., In an AAA rabbit model, interleukin‐10 (IL‐10) treatment inhibited the inflammatory response in the aortic wall and promoted vSMC proliferation. In the tunica media of human thoracic AD patients, SM22 is downregulated, which was associated with promotion of vSMC proliferation in an in vitro assay. Furthermore, upregulated HSP27 has a protective effect on vSMC by promoting vSMC proliferation, suppressing apoptosis and protecting against elevated oxidative stress in human TAD samples.

Contractility of vSMC

The ability of vSMC within the aortic wall to contract is important to maintain vSMC/ECM tensegrity and plays a key role in mechanotransduction. Impaired contractility of vSMC of human AAA patients upon ionomycin stimulation was shown compared with control vSMC. Fibulin‐5‐deficient mice showed diminished vSMC contractility of the thoracic aorta in response to potassium loading, suggesting that sufficient vSMC‐ECM connection is essential for vSMC contraction. Contraction assays in LRP‐1‐deficient mice demonstrated attenuated vasoreactivity, which identified LRP‐1 as a critical modulator of vSMC contraction by regulating calcium signalling in the thoracic aorta.

Inflammation

Vascular smooth muscle cells have the ability to attract inflammatory cells and induce a pro‐inflammatory state in the aortic wall. The infiltration of these inflammatory cells into the aortic wall and their release of cytokines and other mediators affect vSMC functions. An overview of the inflammatory response in the aortic wall regulated by vSMC and affecting vSMC functions during AA and AD development is depicted in Figure 5.

MCP‐1 is an important regulator of the inflammatory response during AAA development and is found in increased levels in human and mouse AAA tissue, compared with control tissue. MCP‐1 in the tunica media can increase MMP‐9 secretion by vSMC and induce more chemokine production by vSMC or macrophage accumulation within the aortic wall. An in vitro vSMC/macrophage co‐culture was used to demonstrate that macrophages primed with MCP‐1 cause higher levels of vSMC apoptosis compared with control macrophages, suggesting that MCP‐1‐primed macrophages are more cytotoxic. Lysyl oxidase (LOX) can suppress secretion of MCP‐1 in cultured vSMC, and enhanced LOX activity in an AAA mouse model prevented macrophage infiltration and AAA progression.

The expression of interleukins (IL), such as IL‐5, IL‐6, and IL‐1beta (IL‐1b), in the aortic wall modulates vSMC functions and is involved in the inflammatory response contributing to AAA development. IL‐5 stimulation of mouse aortic vSMC increased MMP‐2 and MMP‐9, while IL‐5 stimulation of macrophages did not alter MMP expression. Elevated wall tension caused by hypertension resulted in IL‐6 production by vSMC, subsequently causing macrophage infiltration in an AAA mouse model. IL‐1b expression mediates an increased matrix turnover by affecting collagenase and collagen gene expression in human vSMC. Similar findings were reported for TAA tissue, where IL‐1b protein was increased approximately 20‐fold compared with control tissue. Genetic deletion of IL‐1b and IL‐1 receptor in an experimental TAA mouse model demonstrated preserved elastin and vSMC associated with fewer inflammatory cells. In TAD patients, increased IL‐6 downregulated the expression of vSMC contractile proteins alpha‐SMA and SM22alpha and induced autophagy. In human TAD samples, IL‐18 expression was increased, mainly derived from macrophages and partly from T lymphocytes and vSMC. This upregulated IL‐18 expression participated in macrophage‐induced vSMC apoptosis.

The infiltration of different inflammatory cell types into the abdominal aortic wall affects vSMC functions. Accumulated mast cells in AAA mouse lesions release pro‐inflammatory cytokines IL‐6 and IFN‐gamma, which may induce vSMC apoptosis, proteolytic enzyme expression and aortic wall remodelling. In vitro studies with human vSMC showed that both T and natural killer T (NKT) cells adhere to vSMC. While CD4+ T cells enhance vSMC proliferation, CD4+ CD161+ NKT cells inhibit vSMC proliferation by inducing apoptosis, which suggest that these cells contribute to AAA development. In contrast, regulatory T cells were shown to have a protective effect in an AAA mouse model. Regulatory T cells decreased pro‐inflammatory cytokines levels, MMP‐2 and MMP‐9 expression, vSMC apoptosis and oxidative stress, while the expression of the anti‐inflammatory IL‐10 and TGF‐β was increased. Furthermore, regulatory T‐cell treatment in an AAA mouse model decreased expression of the pro‐inflammatory protein cyclooxygenase‐2 in vSMC and macrophages and increased vSMC viability. Patients suffering from bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) disease have an increased risk for TAAD development and rupture of the aortic wall. When comparing gene expression profiles of human BAV and TAV tissue biopsy samples, an immune response activation is only seen in the aortic media of TAV patients, suggesting that inflammation is involved in TAA formation in TAV patients, but not in BAV patients.

Genetic and epigenetic factors

Thoracic aortic aneurysm and dissection pathogenesis is often driven by a genetic component, affecting proteins encoding for the vSMC contractile apparatus and the ECM in the tunica media. In contrast to TAAD, little is known about genetic causes of AAA. A highly efficient method to investigate the pathogenicity of variants of vSMC contractile apparatus proteins is the use of SMC‐like cells generated by transdifferentiation of human dermal fibroblasts. Figure 6 and Table 1 show an overview of mutations affecting vSMC functions and causing TAAD formation.

Mutations affecting the vSMC contractile apparatus

The vSMC contractile apparatus consists of thin SMC‐specific filaments α‐actin (SM α‐actin, encoded by ACTA2) and thick SMC‐specific filament myosin heavy chain dimer (MHC, encoded by MYH11), assembled with two regulatory light chains (LC) and two essential LC. vSMC contraction is initiated by calcium (Ca2+) influx, binding to calmodulin. This Ca2+/calmodulin complex binds to myosin LC kinase (MLCK, encoded by MYLK), leading to phosphorylation of the regulatory LC of the myosin filaments. The force‐generating cycle is activated by myosin ATPase, and the myosin motor heads move along the actin filaments. After vSMC contraction, a decrease in Ca2+ concentration within the cell inactivates MLCK. The myosin regulatory LC is de‐phosphorylated by myosin light LC phosphatase (MLCP), which is controlled by type I cGMP‐dependent protein kinase (PKG‐1, encoded by PRKG1). A schematic overview of the vSMC contraction is shown in Figure 6.

Mutations in genes encoding the vSMC contractile proteins result in reduced force generation and destabilizing the contractile apparatus, which contributes to the development of TAADs. The most common mutations causing familial TAAD are found in ACTA2, causing 14% of all cases.,,,,,,,,, Loss of SM α‐actin filaments in vSMC causes decreased integrin recruitment for cell‐matrix adhesion. This reduced interaction between vSMC and the ECM combined with reduced contractility makes these vSMCs unable to generate force. Mutations in MYH11, encoding the other main protein of the vSMC contractile apparatus myosin, alter contractile vSMC function and may contribute to TAAD development.,,,, Heterozygous gain‐of‐function mutations in PRKG1 are also associated with TAAD., Increased PKG‐1 activity resulted in decreased phosphorylation of myosin regulatory LC and thereby decreased vSMC contraction. Lastly, heterozygous loss‐of‐function mutations in MYLK are associated with familial TAAD.

Mutations affecting the ECM

The contractile apparatus in vSMC is anchored to the ECM by integrin‐containing focal adhesions, called dense plaques. Integrin receptors in these dense plaques bind to elastin through microfibrils, with the large glycoprotein fibrillin‐1 (encoded by FBN1) as the main protein in microfibrils. Heterozygous FBN1 mutations cause the connective tissue disorder Marfan syndrome. Marfan patients tend to be tall, slender and have with hyper‐flexible joints, accompanied by serious complications in organs containing connective tissue. Marfan disease also affects the connective tissue in the aortic wall, which makes them susceptible for TAA, but not AAA formation, at younger age compared with nongenetic TAA patients.

The aortic wall in Marfan patients contains low levels of fibrillin‐1 and undifferentiated vSMC. vSMC detachment from the ECM causes vSMC phenotypic switching and increases expression of MMP‐9 and elastin in a Marfan mouse model. vSMC cultured from Marfan mice showed a more mesenchymal‐like phenotype with impaired force‐generating capacity due to impaired cytoskeleton and focal adhesion organization. These phenotypic changes are also seen in human Marfan vSMC, affecting SM α‐actin, smoothelin, SM22 alpha, calponin‐1 and myocardin (transcription factor essential for vSMC‐specific differentiation), and resulting in greater cellular and ECM stiffness. These studies suggested that loss of vSMC attachment caused by the FBN1 mutations activates a nonproductive programme to synthesize and remodel the ECM.

Fibrillin‐1 does not only play a role in the structural integrity of the aortic wall, but also regulates the bioavailability of TGF‐β. Fibrillin‐1 and microfibrils can together create a reservoir for TGF‐β, maintaining TGF‐β there in an inactive from. Mutations in fibrillin‐1 disrupt the biological scaffolding role of fibrillin‐1, causing an increase in active TGF‐β, thereby activating TGF‐β receptor‐mediated Smad signalling. Increased TGF‐β expression is shown in vSMC of Marfan patients compared with healthy subjects,, leading to the activation of canonical SMAD3 signalling and the noncanonical ERK signalling. The activation of these pathways can model vSMC proliferation, apoptosis, inflammation and phenotypic switching. Furthermore, increased TGF‐β in Marfan patients induced vSMC senescence through excessive ROS generation and increased vSMC apoptosis. The potential role of TGF‐β signalling in AA and AD formation is further described below.

Reactive oxygen species production in vSMC of Marfan mice was found to be anatomically specific, with increased NADPH activity in vSMC derived from the ascending aorta compared with vSMC derived from the descending aorta. ROS produced by vSMC in the tunica media of Marfan patients targets actin‐based cytoskeleton components and regulators of ECM homeostasis.

There are more known mutations affecting ECM proteins, subsequently disturbing vSMC functions and initiating AA or AD development. Ehlers‐Danlos syndrome type IV is characterized by an COL3A1 mutation. A mutation in the LOX gene, encoding for an enzyme that normally cross‐links collagen and elastin molecules in the aortic wall, causes a loss of stability and elasticity of the aortic wall. Loss‐of‐function mutations in MFAP5, encoding for microfibril‐associated glycoprotein 2, which is a component of the ECM interacting with fibrillin‐1, also appear as an underlying cause of familiar TAAD development.

Mutations affecting TGF‐β signalling

Loeys‐Dietz syndrome is characterized by mutations in genes encoding for components of the TFG‐β pathway, including TGF‐β receptor (TGFBR)‐1 and 2. The role of the altered TGF‐β signalling pathway on vSMC function during AA and AD development and progression is complex, and controversial findings have been reported. vSMC explanted from patients with heterozygous mutations in TGFBR2 (encoded by TGFBR2) showed decreased expression of vSMC contractile proteins, which may contribute to TAAD by affecting the contractile function of vSMC. vSMC‐specific deletion of TGFBR2 in adult mice resulted in mild thoracic aneurysmal degeneration, while vSMC‐specific deletion of TGFBR1 in the same mouse model caused severe thoracic aneurysmal degeneration. In contrast to these findings, vSMC‐specific TGFBR2 disruption in an AAA mouse model prevented AAA formation by reduced elastin degradation, vSMC loss, macrophage infiltration and MMP expression. An explanation for these contrasting effects of TGF‐β on the aortic wall can be the different embryological origins of abdominal and thoracic vSMC. Also, genetic variants of SMAD4, the intracellular secondary messenger of the TGF‐β pathway, are reported as promotors of vSMC apoptosis, proteoglycan degradation and reduced contractile protein gene expression in human TAAD pathogenesis., Likewise, SMAD3‐deficient mice developed TAA rapidly by the activation of immune responses, but did not show vSMC loss or MMP activation in vSMC.

In human TAD tissue, TGF‐β stimulation was found to contribute to aortic wall weakening by iinducing vSMC phenotypic switching from a contractile to a synthetic phenotype. In human AAA tissue, TGF‐β mRNA and protein expression are found to be increased compared with control tissue., This overexpression of TGF‐β was associated with reduced vSMC density, caused by more vSMC apoptosis, while vSMC proliferation was reduced. In contrast, another study reports no changes in proliferation of aneurysmal rat vSMC treated with TGF‐β.

Mutations affecting other vSMC functions

FOXE3 encodes for a transcription factor regulating anti‐apoptotic and pro‐survival pathways and FOXE3 mutations were found to contribute to TAAD development. FOXE3‐deficient mice showed reduced vSMC density and impaired vSMC differentiation in the ascending aorta.

Epigenetic changes in vSMC

Not only genetic changes but also epigenetic changes in vSMC are related to AAA,,, TAA, and TAAD pathogenesis. In contrast to genetics, epigenetic changes can modify gene expression without altering the genetic code itself, for example by DNA methylation or histone modification. Sirtuin‐1 is a class III histone deacetylase which is decreased in human AAA samples. Knockout of Sirtuin‐1 in vSMC accelerated formation and rupture of AAA by inducing inflammation and vascular senescence, while Sirtuin‐1 overexpression in vSMC had a protective effect in a mouse model. vSMC collected from human TAA tissue showed increased SMAD2 expression compared with vSMC collected from healthy thoracic tissue, which was dependent on epigenetic regulation of the SMAD2 promotors involving histone modifications., Enhancer of zeste homolog 2 (EZH2) is a methyl transferase of histone H3 that functions as a transcriptional repressor and inhibits autophagic cell death of vSMC during TAAD progression. Epigenetic changes in AA pathogenesis are of interest since these changes can be reversible and altered by environmental factors, such as smoking. Epigenetic changes may therefore explain the link between AA risk factors and AA development.

Regulatory RNAs regulating vSMC functions

MicroRNA (miRNA) are RNA strands of 19–24 nucleotides regulating gene expression, which are involved in AA and AD pathogenesis by modulating different vSMC functions. Table 2 gives an overview of miRNA involved in regulating vSMC functions, and how expression level of these miRNA affects vSMC function. The anatomical location and the species in which these miRNAs were studied are also shown. In AAA pathogenesis, miRNA‐21, miRNA‐26a, miRNA‐28‐5p, miRNA‐129‐5p, miRNA‐155‐5p, miRNA‐195 and miRNA‐504 are reported to be involved in regulation of vSMC apoptosis. miRNA‐155, miRNA‐195, miRNA‐205 and miRNA‐516a‐5p are found to be involved in ECM regeneration and degradation. miRNA‐21, miRNA‐129‐5p, miRNA‐155, miRNA‐195 and miRNA‐504 can regulate vSMC proliferation, while miRNA‐155 can regulate vSMC migration. miRNA‐24, miRNA‐33, miRNA‐155 and miRNA‐195 are involved in regulation of the inflammatory response within the aortic wall.

In TAA pathogenesis, only miRNA‐145 is reported as regulator of ECM remodelling. In TAD pathogenesis, miRNA‐26b, miRNA‐145,, miRNA‐320d and miRNA‐582 can regulate vSMC apoptosis. miRNA‐124, miRNA‐134‐5p and miRNA‐143/145 gene cluster can have a role in regulation of vSMC phenotypic switching. miRNA‐27a, miRNA‐133, miRNA‐134‐5p, miRNA‐145 and miRNA‐146a‐5p are found to be involved in vSMC migration. miRNA‐26b, miRNA‐124, miRNA‐133, miRNA‐145, and miRNA‐146a‐5p are reported as regulators of vSMC proliferation. miRNA‐30a is found to be involved in ECM remodelling by vSMC. In a TAAD mouse model, knockout of miRNA‐21 induced a switch from a contractile to a synthetic vSMC phenotype, due to dysfunctional TGF‐β signalling.

Long noncoding RNA (lnc‐RNA) is defined as transcripts exceeding 200 nucleotides which are not translated into protein. However, they are crucial participants in both AAA and TAA pathogenesis by altering vSMC functions. Table 2 shows an overview of lnc‐RNA involved in regulating vSMC functions during AAA and TAA development and how expression level of these lnc‐RNA affect vSMC function. The anatomical location and the species in which these lnc‐RNA were studied are also shown. In AAA pathogenesis, vSMC apoptosis can be regulated by lnc‐RNA NEAT1, GAS5, H19, plasmacytoma variant translocation 1 (PVT1), LUCAT1 and LINC00473. Lnc‐RNA PVT1 is also a regulator of ECM regeneration and degradation, and the inflammatory response within the aortic wall. Regulators of vSMC proliferation are lnc‐RNA NEAT1, GAS5, LUCAT1 and LINC00473. In TAA pathogenesis, lnc‐RNA LOXL1‐AS, myocardial infarction associated transcript (MIAT), HOX transcript antisense intergenic RNA (HOTAIR), HIF 1alpha antisense RNA and long intergenic noncoding RNA (linc‐RNA) p‐21 are associated with regulation of vSMC apoptosis. Lnc‐RNA LOXL1‐AS, HOTAIR, HIF 1alpha antisense RNA and linc‐RNA p‐21 are reported be involved in regulation of vSMC proliferation, and lnc‐RNA HOTAIR is involved in ECM remodelling.

DISCUSSION AND FUTURE PERSPECTIVES

AA are pathological dilations of the aortic wall, which can rupture and cause internal bleeding. As summarized in this review, previous studies have shown that vSMC dysfunction has a paramount role in aortic wall weakening and subsequent AA and AD formation. Although several attempts have been made to develop pharmacological treatment options for stabilization or prevention of AA and AD, none of them has led to a broadly applicable treatment yet. In case of type B AD, patients are treated with anti‐hypertensive medication but the majority of the patients do not show improvement upon this therapy. Disease progression is unpredictable, which makes it challenging to decide whether patients need surgical repair to prevent rupture. Therefore, more research into the underlying molecular mechanism of vSMC dysfunction in AA and AD progression and development is warranted.

Treatment options based on rodent studies

Targeting the loss of vSMC within the aortic wall caused by apoptosis is a potential treatment strategy. During endovascular repair, a graft is placed within the aortic wall, and seeding these endovascular grafts with vSMC has been shown to have a protective and reparative effect in a rat model. vSMC graft seeding prevented AAA formation, by decreasing elastin degradation and monocyte infiltration in AAA‐prone rats. Likewise, aneurysm diameter stabilized after endovascular seeding of vSMC with aneurysmal aortic xenografts in an AAA rat model by inhibition of the ECM degradation process. The expression of MMP‐1, MMP‐3, MMP‐7, MMP‐9 and MMP‐12 decreased, while the expression of TIMP‐1, TIMP‐2 and TIMP‐3 increased after vSMC seeding. The importance of vSMC in the aortic wall is highlighted by these studies and demonstrates a protective, paracrine effect of endovascular vSMC seeding on the aortic wall. Endovascular AA stent repair combined with the restoration of the healing capability of vSMC could be a promising therapeutic alternative.

The production and activation of proteolytic enzymes by vSMC contribute to AA progression and could therefore be a potential treatment target. Inhibition of ECM degradation by Doxycycline, a nonspecific inhibitor of MMP, gave promising results in rat and mouse studies., However, evidence from clinical studies to confirm this beneficial effect is still lacking and this MMP inhibitor is therefore not used as therapeutic treatment for AA patients yet., Upregulation of other inhibitors of proteolytic enzymes, such as PAI‐1 and TIMP, using gene therapy may also decrease ECM degradation within the aortic wall. Local overexpression of TIMP‐1 in a rat aorta resulted in decreased MMP‐9 and activated MMP‐2, which preserved elastin in the tunica media and prevented aneurysmal degeneration and rupture. Another treatment option would be to target external factors which affect vSMC functions, such as inflammation or oxidative stress. Statins, which are lipid‐lowering drugs, have previously been shown to suppress AAA growth in a mouse model, by having an anti‐inflammatory effect on the aortic wall and reducing ER stress and apoptosis. In humans, an association between statin use and a decreased expansion rate of infrarenal AA was also reported, but this still needs to be confirmed by randomized clinical trials. Additionally, the ability of regulatory miRNA and lnc‐RNA expression to alter gene expression and modulate vSMC functions may be explored to improve vSMC function within the aortic wall and prevent AA formation. miRNA activity can be manipulated by anti‐miRs, blockmiRs or miRNA mimics, delivered by viral vectors, nanoparticles or liposomes. This potential of miRNA as a treatment option was previously shown to be effective for other cardiovascular diseases.

Strength of tissue biobanks, patient‐derived vSMC and in vitro aortic models

So far, none of the above‐described proposed therapeutic treatment options are implemented in the clinic. AA is a heterogeneous and multifactorial disorder with differences in origin and disease progression in every patient, which makes the development of therapeutic AA treatments challenging. To address this challenge, it is necessary to perform in vitro experiments and translational studies on a large number of patient samples. Creating a biobank with patient samples, and specifically vSMC, is needed to define the link between defects in vSMC and clinical characteristics in large cohorts of patients. Our group showed in vitro that contraction of vSMC isolated from AAA patients is impaired compared with healthy control vSMC. Impaired vSMC contraction was mainly seen in patients who were current smokers and who underwent open repair surgery after earlier endovascular repair. However, the underlying mechanism of vSMC contractility reduction leading to AA formation still remains unexplored. More research is needed into the exact proteins and pathways contributing to vSMC contractile dysfunction and the link between these molecular defects and other patient characteristics, such as sex, age and diabetes. Functional studies in human vSMC should be combined with multiple –omics studies (RNA‐seq, proteomics) in large numbers of patient compared with control samples to identify proteins and pathways involved in AA progression, which can be used as potential treatment targets.

Another explanation for the absence of therapeutic AA treatments is the lack of adequate in vitro models. These models, mimicking human disease, can be used to investigate disease progression and effects of therapeutic interventions. vSMC can be generated from stem cells, but this is a time‐consuming and expensive process. Segments of isolated aortic tissue from large animals, maintained in organ culture, can also be used as an in vitro model. This model has the advantage that laminar shear stress can be applied, but the disadvantages that these isolated aortic segments can only be kept in culture for a limited time period. Preclinical 3D cell culture models seeded with patient‐specific SMC can recreate the complex micro‐environment of the aorta in vitro. This model gives the option to study mechanical properties, fibre orientation, ECM production by vSMC and the interaction with other cell types in the aortic wall, such as endothelial cells. However, in this model, the cells lose their original tubular form. Therefore, the complexity of this model can be increased by generation of tubular grafts using a bioreactor to study additional parameters, such as flow. Another method to study aneurysmal disease in vitro is by transdifferentiation of fibroblasts, isolated from skin tissue, into vSMC‐like cells. After conversion of these dermal fibroblasts, mRNA expression of SMC markers within the vSMC‐like cells is comparable to primary human aortic SMC. This noninvasive method is highly efficient to detect gene mutations and molecular defects in vSMC‐like cells, already at an early disease stage before the patient develops AA. Specific molecular defects within individual patients can be diagnosed, and targeting these patient‐specific defects can improve patient outcome. Furthermore, functional measurements of vSMC‐like cells could have the potential to eventually predict characteristics of AA progression, such as aneurysm size growth and chance of rupture, in patients with early AA who have not yet undergone surgery. The above‐mentioned in vitro models, using either biological materials or biological combined with synthetic materials, have an important role in ‘proof of concept studies’, but they require further validation to optimize in vitro aneurysmal disease research.

A last important point to underscore is that recent studies suggest that also endothelial cells play a key role in development and progression of AA and AD. Endothelial dysfunction can activate aortic wall remodelling by release of proteases, or induction of inflammatory and oxidative stress responses.,, Therefore, we want to highlight the importance to consider the interaction between endothelial cells and vSMC while studying aneurysmal disease.

CONCLUSION

In conclusion, our review illustrates the central role of impaired vSMC function in AA and AD development and progression and highlights the stressors and molecular pathways which may be targets for therapeutic interventions. Future research should focus on studies in models, which mimic the individual AA patient and define effects of stressors and interventions in these specific patients. This way, new potential targets for pharmaceutical treatments can be found and better disease progression prediction can be made for both AA and AD in order to improve patient outcome.

CONFLICT OF INTEREST

Not applicable.

AUTHORS’ CONTRIBUTIONS

KR designed and performed the database searches, selected articles found in the database search, wrote the manuscript and designed the figures. TM selected articles found in the database search and revised the manuscript. JCFK designed and performed the database searches. NB, JvV and KKY helped, advised and assisted on the selection of the articles, writing of the manuscript and revised the manuscript. All authors read and approved the final manuscript.

References 244

  1. 1.

    Lederle FA, Johnson GR, Wilson SE, et al. Prevalence and associations of abdominal aortic aneurysm detected through screening. Ann Intern Med. 1997;126:441.

    Not in our library10.7326/0003-4819-126-6-199703150-00004

  2. 2.

    Blanchard JF, Armenian HK, Friesen PP. Risk factors for abdominal aortic aneurysm: results of a case‐control study. Am J Epidemiol. 1999;151(6):575‐583.

    Not in our library10.1093/oxfordjournals.aje.a010245

  3. 3.

    Milewicz DM, Guo DC, Tran‐Fadulu V, et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet. 2008;9:283‐302.

    Not in our library10.1146/annurev.genom.8.080706.092303

  4. 4.

    Sailer AM, Nelemans PJ, Hastie TJ, et al. Prognostic significance of early aortic remodeling in acute uncomplicated type B aortic dissection and intramural hematoma. J Thorac Cardiovasc Surg. 2017;154(4):1192‐1200.

    Not in our library10.1016/j.jtcvs.2017.04.064

  5. 5.

    Assar AN, Zarins CK. Ruptured abdominal aortic aneurysm: a surgical emergency with many clinical presentations. Postgrad Med J. 2009;85(1003):268‐273.

    Not in our library10.1136/pgmj.2008.074666

  6. 6.

    Wanhainen A, Verzini F, Van Herzeele I, et al. European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the management of abdominal aorto‐iliac artery aneurysms. Eur J Vasc Endovasc Surg. 2019;57(1):8‐93.

    Not in our library10.1016/j.ejvs.2018.09.020

  7. 7.

    Durham CA, Cambria RP, Wang LJ, et al. The natural history of medically managed acute type B aortic dissection. J Vasc Surg. 2015;61(5):1192‐1198.

    Not in our library10.1016/j.jvs.2014.12.038

  8. 8.
    Embryonic origins of human vascular smooth muscle cells: implications for in vitro modeling and clinical application · 2014
    No notice
  9. 9.

    Ailawadi G, Moehle CW, Pei H, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg. 2009;138(6):1392‐1399.

    Not in our library10.1016/j.jtcvs.2009.07.075

  10. 10.

    Frismantiene A, Philippova M, Erne P, Resink TJ. Smooth muscle cell‐driven vascular diseases and molecular mechanisms of VSMC plasticity. Cell Signal. 2018;52:48‐64.

    Not in our library10.1016/j.cellsig.2018.08.019

  11. 11.

    Lopez‐Candales A, Holmes DR, Liao S, Scott MJ, Wickline SA, Thompson RW. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol. 1997;150(3):993‐1007.

    Not in our library

  12. 12.

    Zhang J, Schmidt J, Ryschich E, Schumacher H, Allenberg JR. Increased apoptosis and decreased density of medial smooth muscle cells in human abdominal aortic aneurysms. Chin Med J (Engl). 2003;116(10):1549‐1552.

    Not in our library

  13. 13.

    Henderson EL, Geng YJ, Sukhova GK, Whittemore AD, Knox J, Libby P. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation. 1999;99(1):96‐104.

    Not in our library10.1161/01.cir.99.1.96

  14. 14.

    Satta J, Mennander A, Soini Y. Increased medial TUNEL‐positive staining associated with apoptotic bodies is linked to smooth muscle cell diminution during evolution of abdominal aortic aneurysms. Ann Vasc Surg. 2002;16(4):462‐466.

    Not in our library10.1007/s10016-001-0071-2

  15. 15.

    Rowe VL, Stevens SL, Reddick TT, et al. Vascular smooth muscle cell apoptosis in aneurysmal, occlusive, and normal human aortas. J Vasc Surg. 2000;31(3):567‐576.

    Not in our library

  16. 16.

    Yamanouchi D, Morgan S, Stair C, et al. Accelerated aneurysmal dilation associated with apoptosis and inflammation in a newly developed calcium phosphate rodent abdominal aortic aneurysm model. J Vasc Surg. 2012;56(2):455‐461.

    Not in our library10.1016/j.jvs.2012.01.038

  17. 17.

    Wang Q, Shu C, Su J, Li X. A crosstalk triggered by hypoxia and maintained by MCP‐1/miR‐98/IL‐6/p38 regulatory loop between human aortic smooth muscle cells and macrophages leads to aortic smooth muscle cells apoptosis via Stat1 activation. Int J Clin Exp Pathol. 2015;8(3):2670‐2679.

    Not in our library

  18. 18.

    Yamanouchi D, Morgan S, Kato K, Lengfeld J, Zhang F, Liu B. Effects of caspase inhibitor on angiotensin II‐induced abdominal aortic aneurysm in apolipoprotein E‐deficient mice. Arterioscler Thromb Vasc Biol. 2010;30(4):702‐707.

    Not in our library10.1161/atvbaha.109.200527

  19. 19.

    Xue M, Li G, Li D, et al. Up‐regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production. Biosci Rep. 2019;39(11).

    Not in our library10.1042/bsr20191252

  20. 20.

    Morgan S, Yamanouchi D, Harberg C, et al. Elevated protein kinase C‐delta contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling. Arterioscler Thromb Vasc Biol. 2012;32(10):2493‐2502.

    Not in our library10.1161/atvbaha.112.255661

  21. 21.

    Sigala F, Papalambros E, Kotsinas A, et al. Relationship between iNOS expression and aortic cell proliferation and apoptosis in an elastase‐induced model of aorta aneurysm and the effect of 1400 W administration. Surgery. 2005;137(4):447‐456.

    Not in our library10.1016/j.surg.2004.12.003

  22. 22.

    Ni XQ, Lu WW, Zhang JS, et al. Inhibition of endoplasmic reticulum stress by intermedin 1–53 attenuates angiotensin II‐induced abdominal aortic aneurysm in ApoE KO Mice. Endocrine. 2018;62(1):90‐106.

    Not in our library10.1007/s12020-018-1657-6

  23. 23.

    He R, Guo DC, Estrera AL, et al. Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections. J Thorac Cardiovasc Surg. 2006;131(3):671‐678.

    Not in our library10.1016/j.jtcvs.2005.09.018

  24. 24.

    Jia LX, Zhang WM, Zhang HJ, et al. Mechanical stretch‐induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection. J Pathol. 2015;236(3):373‐383.

    Not in our library10.1002/path.4534

  25. 25.

    Acilan C, Serhatli M, Kacar O, et al. Smooth muscle cells isolated from thoracic aortic aneurysms exhibit increased genomic damage, but similar tendency for apoptosis. DNA Cell Biol. 2012;31(10):1523‐1534.

    Not in our library10.1089/dna.2012.1644

  26. 26.

    Adiguzel Z, Arda N, Kacar O, et al. Evaluation of apoptotic molecular pathways for smooth muscle cells isolated from thoracic aortic aneurysms in response to oxidized sterols. Mol Biol Rep. 2014;41(12):7875‐7884.

    Not in our library10.1007/s11033-014-3681-9

  27. 27.

    Durdu S, Deniz GC, Balci D, et al. Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection. Cardiovasc Ther. 2012;30(6):308‐316.

    Not in our library10.1111/1755-5922.12007

  28. 28.

    Jiang WJ, Ren WH, Liu XJ, et al. Disruption of mechanical stress in extracellular matrix is related to Stanford type A aortic dissection through down‐regulation of Yes‐associated protein. Aging (Albany NY). 2016;8(9):1923‐1939.

    Not in our library10.18632/aging.101033

  29. 29.

    Liu T, Xu J, Guo JL, et al. YAP1 up‐regulation inhibits apoptosis of aortic dissection vascular smooth muscle cells. Eur Rev Med Pharmacol Sci. 2017;21(20):4632‐4639.

    Not in our library

  30. 30.

    Rizos IK, Tsoporis JN, Toumpoulis IK, et al. Antiapoptotic effect of beta1 blockers in ascending thoracic aortic smooth muscle cells: the role of HSP70 expression. J Cardiovasc Pharmacol. 2018;72(2):86‐96.

    Not in our library10.1097/fjc.0000000000000596

  31. 31.

    Zou S, Liao M, Yang J, et al. Heat shock protein 27 plays a protective role in thoracic aortic dissection by promoting cell proliferation and inhibiting apoptosis. Cell Mol Biol Lett. 2017;22:24.

    Not in our library10.1186/s11658-017-0056-y

  32. 32.

    Lu H, Sun J, Liang W, et al. Cyclodextrin prevents abdominal aortic aneurysm via activation of vascular smooth muscle cell transcription factor EB. Circulation. 2020;142(5):483‐498.

    Not in our library10.1161/circulationaha.119.044803

  33. 33.
    Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms · 2019
    No notice
  34. 34.

    Farrell K, Simmers P, Mahajan G, et al. Alterations in phenotype and gene expression of adult human aneurysmal smooth muscle cells by exogenous nitric oxide. Exp Cell Res. 2019;384(1):111589.

    Not in our library10.1016/j.yexcr.2019.111589

  35. 35.

    Riches K, Clark E, Helliwell RJ, et al. Progressive development of aberrant smooth muscle cell phenotype in abdominal aortic aneurysm disease. J Vasc Res. 2018;55(1):35‐46.

    Not in our library10.1159/000484088

  36. 36.

    Busch A, Hartmann E, Grimm C, et al. Heterogeneous histomorphology, yet homogeneous vascular smooth muscle cell dedifferentiation, characterize human aneurysm disease. J Vasc Surg. 2017;66(5):1553‐1564.e1556.

    Not in our library10.1016/j.jvs.2016.07.129

  37. 37.

    Lai CH, Chang CW, Lee FT, et al. Targeting vascular smooth muscle cell dysfunction with xanthine derivative KMUP‐3 inhibits abdominal aortic aneurysm in mice. Atherosclerosis. 2020;297:16‐24.

    Not in our library10.1016/j.atherosclerosis.2020.01.029

  38. 38.

    Liang ES, Cheng W, Yang RX, Bai WW, Liu X, Zhao YX. Peptidyl‐prolyl isomerase Pin1 deficiency attenuates angiotensin II‐induced abdominal aortic aneurysm formation in ApoE(‐/‐) mice. J Mol Cell Cardiol. 2018;114:334‐344.

    Not in our library10.1016/j.yjmcc.2017.12.006

  39. 39.

    Zhong L, He X, Si X, et al. SM22alpha (Smooth Muscle 22alpha) prevents aortic aneurysm formation by inhibiting smooth muscle cell phenotypic switching through suppressing reactive oxygen species/NF‐kappaB (nuclear factor‐kappaB). Arterioscler Thromb Vasc Biol. 2019;39(1):e10‐e25.

    Not in our library10.1161/atvbaha.118.311917

  40. 40.

    Moehle CW, Bhamidipati CM, Alexander MR, et al. Bone marrow‐derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation. J Thorac Cardiovasc Surg. 2011;142(6):1567‐1574.

    Not in our library10.1016/j.jtcvs.2011.07.053

  41. 41.

    Peng H, Zhang K, Liu Z, et al. VPO1 modulates vascular smooth muscle cell phenotypic switch by activating extracellular signal‐regulated kinase 1/2 (ERK 1/2) in abdominal aortic aneurysms. J Am Heart Assoc. 2018;7(17):e010069.

    Not in our library10.1161/jaha.118.010069

  42. 42.

    Qin X, He L, Tian M, et al. Smooth muscle‐specific Gs alpha deletion exaggerates angiotensin II‐induced abdominal aortic aneurysm formation in mice in vivo. J Mol Cell Cardiol. 2019;132:49‐59.

    Not in our library10.1016/j.yjmcc.2019.05.002

  43. 43.

    Sachdeva J, Mahajan A, Cheng J, et al. Smooth muscle cell‐specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression. PLoS One. 2017;12(5):e0178538.

    Not in our library10.1371/journal.pone.0178538

  44. 44.

    Tanaskovic I, Lackovic V, Radak D, et al. Ultrastructural characteristics of the vascular wall components of ruptured atherosclerotic abdominal aortic aneurysm. Arch Biol Sci. 2013;65(4):1271‐1278.

    Not in our library

  45. 45.

    Wang S, Jia C. TRPV1 inhibits smooth muscle cell phenotype switching in a mouse model of abdominal aortic aneurysm. Channels (Austin). 2020;14(1):59‐68.

    Not in our library10.1080/19336950.2020.1730020

  46. 46.

    Mourmoura E, Vasilaki A, Giannoukas A, Michalodimitrakis E, Pavlidis P, Tsezou A. Evidence of deregulated cholesterol efflux in abdominal aortic aneurysm. Acta Histochem. 2016;118(2):97‐108.

    Not in our library10.1016/j.acthis.2015.11.012

  47. 47.

    Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of osteoprotegerin with human abdominal aortic aneurysm progression. Circulation. 2005;111(23):3119‐3125.

    Not in our library10.1161/circulationaha.104.464727

  48. 48.

    Moran CS, Jose RJ, Biros E, Golledge J. Osteoprotegerin deficiency limits angiotensin II‐induced aortic dilatation and rupture in the apolipoprotein E‐knockout mouse. Arterioscler Thromb Vasc Biol. 2014;34(12):2609‐2616.

    Not in our library10.1161/atvbaha.114.304587

  49. 49.

    Salmon M, Johnston WF, Woo A, et al. KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation. Circulation. 2013;128(11 Suppl 1):S163‐174.

    Not in our library10.1161/circulationaha.112.000238

  50. 50.

    Mukherjee K, Gitlin JM, Loftin CD. Effectiveness of cyclooxygenase‐2 inhibition in limiting abdominal aortic aneurysm progression in mice correlates with a differentiated smooth muscle cell phenotype. J Cardiovasc Pharmacol. 2012;60(6):520‐529.

    Not in our library10.1097/fjc.0b013e318270b968

  51. 51.

    Malashicheva A, Kostina D, Kostina A, et al. Phenotypic and functional changes of endothelial and smooth muscle cells in thoracic aortic aneurysms. Int J Vasc Med. 2016;2016:3107879.

    Not in our library10.1155/2016/3107879

  52. 52.

    Mao N, Gu T, Shi E, Zhang G, Yu L, Wang C. Phenotypic switching of vascular smooth muscle cells in animal model of rat thoracic aortic aneurysm. Interact Cardiovasc Thorac Surg. 2015;21(1):62‐70.

    Not in our library10.1093/icvts/ivv074

  53. 53.

    Forte A, Della Corte A, Grossi M, et al. Differential expression of proteins related to smooth muscle cells and myofibroblasts in human thoracic aortic aneurysm. Histol Histopathol. 2013;28(6):795‐803.

    Not in our library10.14670/hh-28.795

  54. 54.

    Branchetti E, Poggio P, Sainger R, et al. Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovasc Res. 2013;100(2):316‐324.

    Not in our library10.1093/cvr/cvt205

  55. 55.

    Zheng H, Liu J, Shan J, Xue S. Expression of gax in thoracic aortic aneurysm and its effect on phenotypic transformation of thoracic aortic smooth muscle cells. Int J Clin Exp Med. 2019;12(12):13265‐13273.

    Not in our library

  56. 56.

    Liu R, Lo L, Lay AJ, et al. ARHGAP18 protects against thoracic aortic aneurysm formation by mitigating the synthetic and proinflammatory smooth muscle cell phenotype. Circ Res. 2017;121(5):512‐524.

    Not in our library10.1161/circresaha.117.310692

  57. 57.

    Chiarini A, Onorati F, Marconi M, et al. Studies on sporadic non‐syndromic thoracic aortic aneurysms: 1. Deregulation of Jagged/Notch 1 homeostasis and selection of synthetic/secretor phenotype smooth muscle cells. Eur J Prev Cardiol. 2018;25(1_suppl):42‐50.

    Not in our library10.1177/2047487318759119

  58. 58.

    Huang J, Yamashiro Y, Papke CL, et al. Angiotensin‐converting enzyme‐induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin‐4‐deficient mice. Sci Transl Med. 2013;5(183):183ra158, 181‐111.

    Not in our library10.1126/scitranslmed.3005025

  59. 59.

    Huang J, Davis EC, Chapman SL, et al. Fibulin‐4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res. 2010;106(3):583‐592.

    Not in our library10.1161/circresaha.109.207852

  60. 60.

    Nogi M, Satoh K, Sunamura S, et al. Small GTP‐binding protein GDP dissociation stimulator prevents thoracic aortic aneurysm formation and rupture by phenotypic preservation of aortic smooth muscle cells. Circulation. 2018;138(21):2413‐2433.

    Not in our library10.1161/circulationaha.118.035648

  61. 61.

    Meng YH, Tian C, Liu L, Wang L, Chang Q. Elevated expression of connective tissue growth factor, osteopontin and increased collagen content in human ascending thoracic aortic aneurysms. Vascular. 2014;22(1):20‐27.

    Not in our library10.1177/1708538112472282

  62. 62.

    Lesauskaite V, Tanganelli P, Sassi C, et al. Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors. Hum Pathol. 2001;32(9):1003‐1011.

    Not in our library10.1053/hupa.2001.27107

  63. 63.

    Li G, Wang M, Caulk AW, et al. Chronic mTOR activation induces a degradative smooth muscle cell phenotype. J Clin Invest. 2020;130(3):1233‐1251.

    Not in our library10.1172/jci131048

  64. 64.

    Zhang J, Wang L, Fu W, et al. Smooth muscle cell phenotypic diversity between dissected and unaffected thoracic aortic media. J Cardiovasc Surg (Torino). 2013;54(4):511‐521.

    Not in our library

  65. 65.

    An Z, Liu Y, Song ZG, Tang H, Yuan Y, Xu ZY. Mechanisms of aortic dissection smooth muscle cell phenotype switch. J Thorac Cardiovasc Surg. 2017;154(5):1511‐1521.e1516.

    Not in our library10.1016/j.jtcvs.2017.05.066

  66. 66.

    Liu K, Fang C, Shen Y, et al. Hypoxia‐inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG‐1 signaling. Oncotarget. 2017;8(20):33343‐33352.

    Not in our library10.18632/oncotarget.16448

  67. 67.

    Yan Y, Tan MW, Xue X, Ding XY, Wang GK, Xu ZY. Involvement of Oct4 in the pathogenesis of thoracic aortic dissection via inducing the dedifferentiated phenotype of human aortic smooth muscle cells by directly upregulating KLF5. J Thorac Cardiovasc Surg. 2016;152(3):820‐829.e824.

    Not in our library10.1016/j.jtcvs.2016.05.036

  68. 68.

    Wu HP, Cheng J, Huang W, et al. The roles of phenotypic transformation of vascular smooth muscle cells regulated by AGEs in the thoracic aortic dissection in neonatal rats. Int J Clin Exp Pathol. 2016;9(3):2758‐2764.

    Not in our library

  69. 69.

    Zhao Z, Wang Y, Li S, et al. HSP90 inhibitor 17‐DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch. Am J Transl Res. 2019;11(1):509‐518.

    Not in our library

  70. 70.

    Patel MI, Melrose J, Ghosh P, Appleberg M. Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms. J Vasc Surg. 1996;24(1):82‐92.

    Not in our library10.1016/s0741-5214(96)70148-9

  71. 71.

    Crowther M, Goodall S, Jones JL, Bell PR, Thompson MM. Increased matrix metalloproteinase 2 expression in vascular smooth muscle cells cultured from abdominal aortic aneurysms. J Vasc Surg. 2000;32(3):575‐583.

    Not in our library10.1067/mva.2000.108010

  72. 72.

    Airhart N, Brownstein BH, Cobb JP, et al. Smooth muscle cells from abdominal aortic aneurysms are unique and can independently and synergistically degrade insoluble elastin. J Vasc Surg. 2014;60(4):1033‐1041; discussion 1041–1032.

    Not in our library10.1016/j.jvs.2013.07.097

  73. 73.

    Goodall S, Crowther M, Hemingway DM, Bell PR, Thompson MM. Ubiquitous elevation of matrix metalloproteinase‐2 expression in the vasculature of patients with abdominal aneurysms. Circulation. 2001;104(3):304‐309.

    Not in our library10.1161/01.cir.104.3.304

  74. 74.

    Goodall S, Porter KE, Bell PR, Thompson MM. Enhanced invasive properties exhibited by smooth muscle cells are associated with elevated production of MMP‐2 in patients with aortic aneurysms. Eur J Vasc Endovasc Surg. 2002;24(1):72‐80.

    Not in our library10.1053/ejvs.2002.1675

  75. 75.

    Sinha I, Hannawa KK, Eliason JL, et al. Early MT‐1 MMP expression following elastase exposure is associated with increased cleaved MMP‐2 activity in experimental rodent aortic aneurysms. Surgery. 2004;136(2):176‐182.

    Not in our library10.1016/j.surg.2004.04.010

  76. 76.

    Gacchina CE, Deb P, Barth JL, Ramamurthi A. Elastogenic inductability of smooth muscle cells from a rat model of late stage abdominal aortic aneurysms. Tissue Eng Part A. 2011;17(13–14):1699‐1711.

    Not in our library10.1089/ten.tea.2010.0526

  77. 77.

    McMillan WD, Patterson BK, Keen RR, Pearce WH. In situ localization and quantification of seventy‐two‐kilodalton type IV collagenase in aneurysmal, occlusive, and normal aorta. J Vasc Surg. 1995;22(3):295‐305.

    Not in our library10.1016/s0741-5214(95)70144-3

  78. 78.

    Kothapalli CR, Gacchina CE, Ramamurthi A. Utility of hyaluronan oligomers and transforming growth factor‐beta1 factors for elastic matrix regeneration by aneurysmal rat aortic smooth muscle cells. Tissue Eng Part A. 2009;15(11):3247‐3260.

    Not in our library10.1089/ten.tea.2008.0593

  79. 79.

    Vasic N, Glumac S, Pejic S, et al. Expression of matrix metalloproteinases and endogenous inhibitors in abdominal aortic aneurysm and aortoiliac occlusive disease (syndrome leriche). Folia Biol (Praha). 2017;63(5–6):209‐216.

    Not in our library10.14712/fb2017063050209

  80. 80.

    Annabi B, Shedid D, Ghosn P, et al. Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms. J Vasc Surg. 2002;35(3):539‐546.

    Not in our library10.1067/mva.2002.121124

  81. 81.

    McMillan WD, Patterson BK, Keen RR, Shively VP, Cipollone M, Pearce WH. In situ localization and quantification of mRNA for 92‐kD type IV collagenase and its inhibitor in aneurysmal, occlusive, and normal aorta. Arterioscler Thromb Vasc Biol. 1995;15(8):1139‐1144.

    Not in our library10.1161/01.atv.15.8.1139

  82. 82.

    Verschuren L, Lindeman JH, van Bockel JH, Abdul‐Hussien H, Kooistra T, Kleemann R. Up‐regulation and coexpression of MIF and matrix metalloproteinases in human abdominal aortic aneurysms. Antioxid Redox Signal. 2005;7(9–10):1195‐1202.

    Not in our library10.1089/ars.2005.7.1195

  83. 83.

    Reeps C, Pelisek J, Seidl S, et al. Inflammatory infiltrates and neovessels are relevant sources of MMPs in abdominal aortic aneurysm wall. Pathobiology. 2009;76(5):243‐252.

    Not in our library10.1159/000228900

  84. 84.

    Lyon CA, Williams H, Bianco R, et al. Aneurysm severity is increased by combined Mmp‐7 deletion and N‐cadherin mimetic (EC4‐Fc) over‐expression. Sci Rep. 2017;7(1):17342.

    Not in our library10.1038/s41598-017-17700-8

  85. 85.

    Mao D, Lee JK, VanVickle SJ, Thompson RW. Expression of collagenase‐3 (MMP‐13) in human abdominal aortic aneurysms and vascular smooth muscle cells in culture. Biochem Biophys Res Commun. 1999;261(3):904‐910.

    Not in our library10.1006/bbrc.1999.1142

  86. 86.

    Crowther M, Goodall S, Jones JL, Bell PR, Thompson MM. Localization of matrix metalloproteinase 2 within the aneurysmal and normal aortic wall. Br J Surg. 2002;87(10):1391‐1400.

    Not in our library10.1046/j.1365-2168.2000.01554.x

  87. 87.

    Wang C, Chang Q, Sun X, et al. Angiotensin II induces an increase in matrix metalloproteinase 2 expression in aortic smooth muscle cells of ascending thoracic aortic aneurysms through JNK, ERK1/2, and p38 MAPK activation. J Cardiovasc Pharmacol. 2015;66(3):285‐293.

    Not in our library10.1097/fjc.0000000000000276

  88. 88.

    Wang C, Qian X, Sun X, Chang Q. Angiotensin II increases matrix metalloproteinase 2 expression in human aortic smooth muscle cells via AT1R and ERK1/2. Exp Biol Med (Maywood). 2015;240(12):1564‐1571.

    Not in our library10.1177/1535370215576312

  89. 89.

    Wang L, Zhang J, Fu W, Guo D, Jiang J, Wang Y. Association of smooth muscle cell phenotypes with extracellular matrix disorders in thoracic aortic dissection. J Vasc Surg. 2012;56(6):1698‐1709, 1709.e1691.

    Not in our library10.1016/j.jvs.2012.05.084

  90. 90.

    Ren W, Liu Y, Wang X, et al. The complement C3a–C3aR axis promotes development of thoracic aortic dissection via regulation of MMP2 expression. J Immunol. 2018;200(5):1829‐1838.

    Not in our library10.4049/jimmunol.1601386

  91. 91.

    Yuan Y, Wang C, Xu J, Tao J, Xu Z, Huang S. BRG1 overexpression in smooth muscle cells promotes the development of thoracic aortic dissection. BMC Cardiovasc Disord. 2014;14:144.

    Not in our library10.1186/1471-2261-14-144

  92. 92.

    Shen M, Lee J, Basu R, et al. Divergent roles of matrix metalloproteinase 2 in pathogenesis of thoracic aortic aneurysm. Arterioscler Thromb Vasc Biol. 2015;35(4):888‐898.

    Not in our library10.1161/atvbaha.114.305115

  93. 93.

    Martin‐Alonso M, Garcia‐Redondo AB, Guo D, et al. Deficiency of MMP17/MT4‐MMP proteolytic activity predisposes to aortic aneurysm in mice. Circ Res. 2015;117(2):e13‐26.

    Not in our library10.1161/circresaha.117.305108

  94. 94.

    Lipp C, Lohoefer F, Reeps C, et al. Expression of a disintegrin and metalloprotease in human abdominal aortic aneurysms. J Vasc Res. 2012;49(3):198‐206.

    Not in our library10.1159/000332959

  95. 95.

    Zhai H, Qi X, Li Z, et al. TIMP3 suppresses the proliferation and migration of SMCs from the aortic neck of atherosclerotic AAA in rabbits, via decreased MMP2 and MMP9 activity, and reduced TNFalpha expression. Mol Med Rep. 2018;18(2):2061‐2067.

    Not in our library10.3892/mmr.2018.9224

  96. 96.

    Bumdelger B, Kokubo H, Kamata R, et al. Induction of Timp1 in smooth muscle cells during development of abdominal aortic aneurysms. Hiroshima J Med Sci. 2013;62(3):63‐67.

    Not in our library

  97. 97.

    Ishii T, Asuwa N. Collagen and elastin degradation by matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase in aortic dissection. Hum Pathol. 2000;31(6):640‐646.

    Not in our library10.1053/hupa.2000.7642

  98. 98.

    Kawai T, Takayanagi T, Forrester SJ, et al. Vascular ADAM17 (a disintegrin and metalloproteinase domain 17) is required for angiotensin II/beta‐aminopropionitrile‐induced abdominal aortic aneurysm. Hypertension. 2017;70(5):959‐963.

    Not in our library10.1161/hypertensionaha.117.09822

  99. 99.

    Shen M, Hu M, Fedak PWM, Oudit GY, Kassiri Z. Cell‐specific functions of ADAM17 regulate the progression of thoracic aortic aneurysm. Circ Res. 2018;123(3):372‐388.

    Not in our library10.1161/circresaha.118.313181

  100. 100.

    Ren P, Zhang L, Xu G, et al. ADAMTS‐1 and ADAMTS‐4 levels are elevated in thoracic aortic aneurysms and dissections. Ann Thorac Surg. 2013;95(2):570‐577.

    Not in our library10.1016/j.athoracsur.2012.10.084

  101. 101.

    Klaus V, Schmies F, Reeps C, et al. Cathepsin S is associated with degradation of collagen I in abdominal aortic aneurysm. Vasa. 2018;47(4):285‐293.

    Not in our library10.1024/0301-1526/a000701

  102. 102.

    Liu J, Sukhova GK, Yang JT, et al. Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. Atherosclerosis. 2006;184(2):302‐311.

    Not in our library10.1016/j.atherosclerosis.2005.05.012

  103. 103.

    Lohoefer F, Reeps C, Lipp C, et al. Quantitative expression and localization of cysteine and aspartic proteases in human abdominal aortic aneurysms. Exp Mol Med. 2014;46:e95.

    Not in our library10.1038/emm.2014.20

  104. 104.

    Lohoefer F, Reeps C, Lipp C, et al. Histopathological analysis of cellular localization of cathepsins in abdominal aortic aneurysm wall. Int J Exp Pathol. 2012;93(4):252‐258.

    Not in our library10.1111/j.1365-2613.2012.00819.x

  105. 105.

    Sun J, Sukhova GK, Zhang J, et al. Cathepsin K deficiency reduces elastase perfusion‐induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol. 2012;32(1):15‐23.

    Not in our library10.1161/atvbaha.111.235002

  106. 106.

    Qin Y, Cao X, Guo J, et al. Deficiency of cathepsin S attenuates angiotensin II‐induced abdominal aortic aneurysm formation in apolipoprotein E‐deficient mice. Cardiovasc Res. 2012;96(3):401‐410.

    Not in our library10.1093/cvr/cvs263

  107. 107.

    Sun J, Sukhova GK, Zhang J, et al. Cathepsin L activity is essential to elastase perfusion‐induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol. 2011;31(11):2500‐2508.

    Not in our library10.1161/atvbaha.111.230201

  108. 108.

    Shi GP, Sukhova GK, Grubb A, et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest. 1999;104(9):1191‐1197.

    Not in our library10.1172/jci7709

  109. 109.

    Schulte S, Sun J, Libby P, et al. Cystatin C deficiency promotes inflammation in angiotensin II‐induced abdominal aortic aneurisms in atherosclerotic mice. Am J Pathol. 2010;177(1):456‐463.

    Not in our library10.2353/ajpath.2010.090381

  110. 110.

    Louwrens HD, Kwaan HC, Pearce WH, Yao JS, Verrusio E. Plasminogen activator and plasminogen activator inhibitor expression by normal and aneurysmal human aortic smooth muscle cells in culture. Eur J Vasc Endovasc Surg. 1995;10(3):289‐293.

    Not in our library10.1016/s1078-5884(05)80044-9

  111. 111.

    Allaire E, Hasenstab D, Kenagy RD, Starcher B, Clowes MM, Clowes AW. Prevention of aneurysm development and rupture by local overexpression of plasminogen activator inhibitor‐1. Circulation. 1998;98(3):249‐255.

    Not in our library10.1161/01.cir.98.3.249

  112. 112.

    Borges LF, Gomez D, Quintana M, et al. Fibrinolytic activity is associated with presence of cystic medial degeneration in aneurysms of the ascending aorta. Histopathology. 2010;57(6):917‐932.

    Not in our library10.1111/j.1365-2559.2010.03719.x

  113. 113.

    Boukais K, Borges LF, Venisse L, et al. Clearance of plasmin‐PN‐1 complexes by vascular smooth muscle cells in human aneurysm of the ascending aorta. Cardiovasc Pathol. 2018;32:15‐25.

    Not in our library10.1016/j.carpath.2017.10.002

  114. 114.

    Gomez D, Kessler K, Borges LF, et al. Smad2‐dependent protease nexin‐1 overexpression differentiates chronic aneurysms from acute dissections of human ascending aorta. Arterioscler Thromb Vasc Biol. 2013;33(9):2222‐2232.

    Not in our library10.1161/atvbaha.113.301327

  115. 115.

    Liao S, Curci JA, Kelley BJ, Sicard GA, Thompson RW. Accelerated replicative senescence of medial smooth muscle cells derived from abdominal aortic aneurysms compared to the adjacent inferior mesenteric artery. J Surg Res. 2000;92(1):85‐95.

    Not in our library10.1006/jsre.2000.5878

  116. 116.

    Emeto TI, Moxon JV, Biros E, et al. Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti‐proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2. Clin Sci (Lond). 2014;126(7):517‐527.

    Not in our library10.1042/cs20130425

  117. 117.

    Hoshina K, Sho E, Sho M, Nakahashi TK, Dalman RL. Wall shear stress and strain modulate experimental aneurysm cellularity. J Vasc Surg. 2003;37(5):1067‐1074.

    Not in our library10.1016/s0741-5214(03)70052-4

  118. 118.

    Sho E, Sho M, Nanjo H, Kawamura K, Masuda H, Dalman RL. Comparison of cell‐type‐specific vs transmural aortic gene expression in experimental aneurysms. J Vasc Surg. 2005;41(5):844‐852.

    Not in our library10.1016/j.jvs.2005.02.027

  119. 119.

    Zhu H, Qu X, Zhang C, Yu Y. Interleukin‐10 promotes proliferation of vascular smooth muscle cells by inhibiting inflammation in rabbit abdominal aortic aneurysm. Int J Clin Exp Pathol. 2019;12(4):1260‐1271.

    Not in our library

  120. 120.

    Sun Y, Zhao Z, Hou L, et al. The regulatory role of smooth muscle 22 on the proliferation of aortic smooth muscle cells participates in the development of aortic dissection. J Vasc Surg. 2017;66(3):875‐882.

    Not in our library10.1016/j.jvs.2016.02.063

  121. 121.

    Bogunovic N, Meekel JP, Micha D, Blankensteijn JD, Hordijk PL, Yeung KK. Impaired smooth muscle cell contractility as a novel concept of abdominal aortic aneurysm pathophysiology. Sci Rep. 2019;9(1):6837.

    Not in our library10.1038/s41598-019-43322-3

  122. 122.

    Murtada SI, Ferruzzi J, Yanagisawa H, Humphrey JD. Reduced biaxial contractility in the descending thoracic aorta of fibulin‐5 deficient mice. J Biomech Eng. 2016;138(5):051008.

    Not in our library10.1115/1.4032938

  123. 123.

    Au DT, Ying Z, Hernandez‐Ochoa EO, et al. LRP1 (low‐density lipoprotein receptor‐related protein 1) regulates smooth muscle contractility by modulating Ca(2+) signaling and expression of cytoskeleton‐related proteins. Arterioscler Thromb Vasc Biol. 2018;38(11):2651‐2664.

    Not in our library10.1161/atvbaha.118.311197

  124. 124.

    Yang CQ, Li W, Li SQ, et al. MCP‐1 stimulates MMP‐9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells. Cell Physiol Biochem. 2014;34(2):266‐276.

    Not in our library10.1159/000362997

  125. 125.

    Colonnello JS, Hance KA, Shames ML, et al. Transient exposure to elastase induces mouse aortic wall smooth muscle cell production of MCP‐1 and RANTES during development of experimental aortic aneurysm. J Vasc Surg. 2003;38(1):138‐146.

    Not in our library10.1016/s0741-5214(03)00125-3

  126. 126.

    Akerman AW, Stroud RE, Barrs RW, et al. Elevated wall tension initiates interleukin‐6 expression and abdominal aortic dilation. Ann Vasc Surg. 2018;46:193‐204.

    Not in our library10.1016/j.avsg.2017.10.001

  127. 127.
    Monocyte chemoattractant protein-1 (MCP-1) regulates macrophage cytotoxicity in abdominal aortic aneurysm. · 2014
    Not checked
  128. 128.

    Onoda M, Yoshimura K, Aoki H, et al. Lysyl oxidase resolves inflammation by reducing monocyte chemoattractant protein‐1 in abdominal aortic aneurysm. Atherosclerosis. 2010;208(2):366‐369.

    Not in our library10.1016/j.atherosclerosis.2009.07.036

  129. 129.

    Xu J, Ehrman B, Graham LM, Eagleton MJ. Interleukin‐5 is a potential mediator of angiotensin II‐induced aneurysm formation in apolipoprotein E knockout mice. J Surg Res. 2012;178(1):512‐518.

    Not in our library10.1016/j.jss.2011.12.016

  130. 130.

    Mamun A, Yokoyama U, Saito J, et al. A selective antagonist of prostaglandin E receptor subtype 4 attenuates abdominal aortic aneurysm. Physiol Rep. 2018;6(18):e13878.

    Not in our library10.14814/phy2.13878

  131. 131.

    Keen RR, Nolan KD, Cipollone M, et al. Interleukin‐1 beta induces differential gene expression in aortic smooth muscle cells. J Vasc Surg. 1994;20(5):774‐784; discussion 784–776.

    Not in our library10.1016/s0741-5214(94)70165-2

  132. 132.

    Johnston WF, Salmon M, Pope NH, et al. Inhibition of interleukin‐1beta decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms. Circulation. 2014;130(11 Suppl 1):S51‐59.

    Not in our library10.1161/circulationaha.113.006800

  133. 133.

    An Z, Qiao F, Lu Q, et al. Interleukin‐6 downregulated vascular smooth muscle cell contractile proteins via ATG4B‐mediated autophagy in thoracic aortic dissection. Heart Vessels. 2017;32(12):1523‐1535.

    Not in our library10.1007/s00380-017-1054-8

  134. 134.

    Hu H, Zhang G, Hu H, et al. Interleukin‐18 expression increases in the aorta and plasma of patients with acute aortic dissection. Mediators Inflamm. 2019;2019:8691294.

    Not in our library10.1155/2019/8691294

  135. 135.

    Sun J, Sukhova GK, Yang M, et al. Mast cells modulate the pathogenesis of elastase‐induced abdominal aortic aneurysms in mice. J Clin Invest. 2007;117(11):3359‐3368.

    Not in our library10.1172/jci31311

  136. 136.

    Chan WL, Pejnovic N, Hamilton H, et al. Atherosclerotic abdominal aortic aneurysm and the interaction between autologous human plaque‐derived vascular smooth muscle cells, type 1 NKT, and helper T cells. Circ Res. 2005;96(6):675‐683.

    Not in our library10.1161/01.res.0000160543.84254.f1

  137. 137.

    Meng X, Yang J, Zhang K, et al. Regulatory T cells prevent angiotensin II‐induced abdominal aortic aneurysm in apolipoprotein E knockout mice. Hypertension. 2014;64(4):875‐882.

    Not in our library10.1161/hypertensionaha.114.03950

  138. 138.

    Liu B, Kong J, An G, Zhang K, Qin W, Meng X. Regulatory T cells protected against abdominal aortic aneurysm by suppression of the COX‐2 expression. J Cell Mol Med. 2019;23(10):6766‐6774.

    Not in our library10.1111/jcmm.14554

  139. 139.

    Folkersen L, Wagsater D, Paloschi V, et al. Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: the ASAP study. Mol Med. 2011;17(11–12):1365‐1373.

    Not in our library10.2119/molmed.2011.00286

  140. 140.

    van de Luijtgaarden KM, Heijsman D, Maugeri A, et al. First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. Hum Genet. 2015;134(8):881‐893.

    Not in our library10.1007/s00439-015-1567-0

  141. 141.

    Bogunovic N, Musters RJP, Micha D, et al. Transdifferentiation of human dermal fibroblasts to smooth muscle like cells: a novel method to study the effect of MYH11 and ACTA2 variants in the aortic aneurysm wall. Vascular. 2016;24(1):31.25757609

    Not in our library

  142. 142.

    Chen J, Peters A, Papke CL, et al. Loss of smooth muscle alpha‐actin leads to NF‐kappaB‐dependent increased sensitivity to angiotensin II in smooth muscle cells and aortic enlargement. Circ Res. 2017;120(12):1903‐1915.

    Not in our library10.1161/circresaha.117.310563

  143. 143.

    Lu H, Fagnant PM, Bookwalter CS, Joel P, Trybus KM. Vascular disease‐causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin. Proc Natl Acad Sci USA. 2015;112(31):E4168‐4177.

    Not in our library10.1073/pnas.1507587112

  144. 144.

    Massett MP, Bywaters BC, Gibbs HC, et al. Loss of smooth muscle alpha‐actin effects on mechanosensing and cell‐matrix adhesions. Expe Biol Med. 2020;245(4):374‐384.

    Not in our library10.1177/1535370220903012

  145. 145.

    Cheng J, Zhou X, Jiang X, Sun T. Deletion of ACTA2 in mice promotes angiotensin II induced pathogenesis of thoracic aortic aneurysms and dissections. J Thorac Dis. 2018;10(8):4733‐4740.

    Not in our library10.21037/jtd.2018.07.75

  146. 146.

    Guo DC, Pannu H, Tran‐Fadulu V, et al. Mutations in smooth muscle alpha‐actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39(12):1488‐1493.

    Not in our library10.1038/ng.2007.6

  147. 147.

    Malloy LE, Wen KK, Pierick AR, et al. Thoracic aortic aneurysm (TAAD)‐causing mutation in actin affects formin regulation of polymerization. J Biol Chem. 2012;287(34):28398‐28408.

    Not in our library10.1074/jbc.m112.371914

  148. 148.

    Renard M, Callewaert B, Baetens M, et al. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFbeta signaling in FTAAD. Int J Cardiol. 2013;165(2):314‐321.

    Not in our library10.1016/j.ijcard.2011.08.079

  149. 149.

    Papke CL, Cao J, Kwartler CS, et al. Smooth muscle hyperplasia due to loss of smooth muscle alpha‐actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet‐derived growth factor receptor‐beta. Hum Mol Genet. 2013;22(15):3123‐3137.

    Not in our library10.1093/hmg/ddt167

  150. 150.

    Guo DC, Papke CL, Tran‐Fadulu V, et al. Mutations in smooth muscle alpha‐actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84(5):617‐627.

    Not in our library10.1016/j.ajhg.2009.04.007

  151. 151.

    Hoffjan S, Waldmuller S, Blankenfeldt W, et al. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011;19(5):520‐524.

    Not in our library10.1038/ejhg.2010.239

  152. 152.

    Zhu L, Vranckx R, Khau Van Kien P, et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38(3):343‐349.

    Not in our library10.1038/ng1721

  153. 153.

    Pannu H, Tran‐Fadulu V, Papke CL, et al. MYH11 mutations result in a distinct vascular pathology driven by insulin‐like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16(20):2453‐2462.

    Not in our library10.1093/hmg/ddm201

  154. 154.

    Kuang SQ, Kwartler CS, Byanova KL, et al. Rare, nonsynonymous variant in the smooth muscle‐specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells. Circ Res. 2012;110(11):1411‐1422.

    Not in our library10.1161/circresaha.111.261743

  155. 155.

    Bellini C, Wang S, Milewicz DM, Humphrey JD. Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity. J Biomech. 2015;48(1):113‐121.

    Not in our library10.1016/j.jbiomech.2014.10.031

  156. 156.

    Guo DC, Regalado E, Casteel DE, et al. Recurrent gain‐of‐function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet. 2013;93(2):398‐404.

    Not in our library10.1016/j.ajhg.2013.06.019

  157. 157.

    Gago‐Diaz M, Blanco‐Verea A, Teixido G, et al. PRKG1 and genetic diagnosis of early‐onset thoracic aortic disease. Eur J Clin Invest. 2016;46(9):787‐794.

    Not in our library10.1111/eci.12662

  158. 158.

    Wang L, Guo DC, Cao J, et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87(5):701‐707.

    Not in our library10.1016/j.ajhg.2010.10.006

  159. 159.

    Grewal N, Gittenberger‐de Groot AC. Pathogenesis of aortic wall complications in Marfan syndrome. Cardiovasc Pathol. 2018;33:62‐69.

    Not in our library10.1016/j.carpath.2018.01.005

  160. 160.

    Bunton TE, Biery NJ, Myers L, Gayraud B, Ramirez F, Dietz HC. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ Res. 2001;88(1):37‐43.

    Not in our library10.1161/01.res.88.1.37

  161. 161.

    Nolasco P, Fernandes CG, Ribeiro‐Silva JC, et al. Impaired vascular smooth muscle cell force‐generating capacity and phenotypic deregulation in Marfan Syndrome mice. Biochim Biophys Acta Mol Basis Dis. 2020;1866(1):165587.

    Not in our library10.1016/j.bbadis.2019.165587

  162. 162.

    Crosas‐Molist E, Meirelles T, Lopez‐Luque J, et al. Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome. Arterioscler Thromb Vasc Biol. 2015;35(4):960‐972.

    Not in our library10.1161/atvbaha.114.304412

  163. 163.

    Chaudhry SS, Cain SA, Morgan A, Dallas SL, Shuttleworth CA, Kielty CM. Fibrillin‐1 regulates the bioavailability of TGFbeta1. J Cell Biol. 2007;176(3):355‐367.

    Not in our library10.1083/jcb.200608167

  164. 164.

    Nataatmadja M, West J, Prabowo S, West M. Angiotensin II receptor antagonism reduces transforming growth factor beta and smad signaling in thoracic aortic aneurysm. Ochsner J. 2013;13(1):42‐48.

    Not in our library

  165. 165.

    You W, Hong Y, He H, et al. TGF‐beta mediates aortic smooth muscle cell senescence in Marfan syndrome. Aging (Albany NY). 2019;11(11):3574‐3584.

    Not in our library10.18632/aging.101998

  166. 166.

    Pedroza AJ, Koyano T, Trojan J, et al. Divergent effects of canonical and non‐canonical TGF‐beta signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms. J Cell Mol Med. 2020;24(3):2369‐2383.

    Not in our library10.1111/jcmm.14921

  167. 167.

    Nataatmadja M, West J, West M. Overexpression of transforming growth factor‐beta is associated with increased hyaluronan content and impairment of repair in Marfan syndrome aortic aneurysm. Circulation. 2006;114(1 Suppl):I371‐377.

    Not in our library10.1161/circulationaha.105.000927

  168. 168.

    Emrich F, Penov K, Arakawa M, et al. Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation. J Cell Mol Med. 2019;23(10):7000‐7009.

    Not in our library10.1111/jcmm.14587

  169. 169.

    Jimenez‐Altayo F, Meirelles T, Crosas‐Molist E, et al. Redox stress in Marfan syndrome: dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm. Free Radic Biol Med. 2018;118:44‐58.

    Not in our library10.1016/j.freeradbiomed.2018.02.023

  170. 170.

    D'Hondt S, Van Damme T, Malfait F. Vascular phenotypes in nonvascular subtypes of the Ehlers‐Danlos syndrome: a systematic review. Genet Med. 2018;20(6):562‐573.

    Not in our library10.1038/gim.2017.138

  171. 171.

    Lee VS, Halabi CM, Hoffman EP, et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci USA. 2016;113(31):8759‐8764.

    Not in our library10.1073/pnas.1601442113

  172. 172.

    Barbier M, Gross MS, Aubart M, et al. MFAP5 loss‐of‐function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. Am J Hum Genet. 2014;95(6):736‐743.

    Not in our library10.1016/j.ajhg.2014.10.018

  173. 173.

    Van Laer L, Dietz H, Loeys B. Loeys‐dietz syndrome. Adv Exp Med Biol. 2014;802:95‐105.

    Not in our library10.1007/978-94-007-7893-1_7

  174. 174.

    Inamoto S, Kwartler CS, Lafont AL, et al. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovasc Res. 2010;88(3):520‐529.

    Not in our library10.1093/cvr/cvq230

  175. 175.

    Yang P, Schmit BM, Fu C, et al. Smooth muscle cell‐specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events. Sci Rep. 2016;6:35444.

    Not in our library10.1038/srep35444

  176. 176.

    Gao F, Chambon P, Offermanns S, et al. Disruption of TGF‐beta signaling in smooth muscle cell prevents elastase‐induced abdominal aortic aneurysm. Biochem Biophys Res Commun. 2014;454(1):137‐143.

    Not in our library10.1016/j.bbrc.2014.10.053

  177. 177.
    A Functional Variant of SMAD4 Enhances Thoracic Aortic Aneurysm and Dissection Risk through Promoting Smooth Muscle Cell Apoptosis and Proteoglycan Degradation · 2017
    Not checked
  178. 178.

    Duan XY, Guo DC, Regalado ES, et al. SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2019;27(7):1054‐1060.

    Not in our library10.1038/s41431-019-0357-x

  179. 179.

    van der Pluijm I, van Vliet N, von der Thusen JH, et al. Defective connective tissue remodeling in Smad3 mice leads to accelerated aneurysmal growth through disturbed downstream TGF‐beta signaling. EBioMedicine. 2016;12:280‐294.

    Not in our library10.1016/j.ebiom.2016.09.006

  180. 180.

    Zhu SB, Zhu J, Zhou ZZ, Xi EP, Wang RP, Zhang Y. TGF‐beta1 induces human aortic vascular smooth muscle cell phenotype switch through PI3K/AKT/ID2 signaling. Am J Transl Res. 2015;7(12):2764‐2774.

    Not in our library

  181. 181.

    Doyle AJ, Redmond EM, Gillespie DL, et al. Differential expression of Hedgehog/Notch and transforming growth factor‐beta in human abdominal aortic aneurysms. J Vasc Surg. 2015;62(2):464‐470.

    Not in our library10.1016/j.jvs.2014.02.053

  182. 182.

    Fukui D, Miyagawa S, Soeda J, Tanaka K, Urayama H, Kawasaki S. Overexpression of transforming growth factor beta1 in smooth muscle cells of human abdominal aortic aneurysm. Eur J Vasc Endovasc Surg. 2003;25(6):540‐545.

    Not in our library10.1053/ejvs.2002.1857

  183. 183.

    Kuang SQ, Medina‐Martinez O, Guo DC, et al. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest. 2016;126(3):948‐961.

    Not in our library10.1172/jci83778

  184. 184.

    Toghill BJ, Saratzis A, Freeman PJ, Sylvius N, Bown MJ. SMYD2 promoter DNA methylation is associated with abdominal aortic aneurysm (AAA) and SMYD2 expression in vascular smooth muscle cells. Clin Epigenetics. 2018;10:29.

    Not in our library10.1186/s13148-018-0460-9

  185. 185.

    Vinh A, Gaspari TA, Liu HB, Dousha LF, Widdop RE, Dear AE. A novel histone deacetylase inhibitor reduces abdominal aortic aneurysm formation in angiotensin II‐infused apolipoprotein E‐deficient mice. J Vasc Res. 2008;45(2):143‐152.

    Not in our library10.1159/000110041

  186. 186.

    Chen HZ, Wang F, Gao P, et al. Age‐associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm. Circ Res. 2016;119(10):1076‐1088.

    Not in our library10.1161/circresaha.116.308895

  187. 187.

    Gomez D, Kessler K, Michel JB, Vranckx R. Modifications of chromatin dynamics control Smad2 pathway activation in aneurysmal smooth muscle cells. Circ Res. 2013;113(7):881‐890.

    Not in our library10.1161/circresaha.113.301989

  188. 188.

    Gomez D, Coyet A, Ollivier V, et al. Epigenetic control of vascular smooth muscle cells in Marfan and non‐Marfan thoracic aortic aneurysms. Cardiovasc Res. 2011;89(2):446‐456.

    Not in our library10.1093/cvr/cvq291

  189. 189.

    Li R, Yi X, Wei X, et al. EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection. Cell Death Dis. 2018;9(2):180.

    Not in our library10.1038/s41419-017-0213-2

  190. 190.

    Maegdefessel L, Azuma J, Toh R, et al. MicroRNA‐21 blocks abdominal aortic aneurysm development and nicotine‐augmented expansion. Sci Transl Med. 2012;4(122):122ra122.

    Not in our library10.1126/scitranslmed.3003441

  191. 191.

    Peng J, He X, Zhang L, Liu P. MicroRNA26a protects vascular smooth muscle cells against H2O2 induced injury through activation of the PTEN/AKT/mTOR pathway. Int J Mol Med. 2018;42(3):1367‐1378.

    Not in our library10.3892/ijmm.2018.3746

  192. 192.

    Yue J, Zhu T, Yang J, et al. CircCBFB‐mediated miR‐28‐5p facilitates abdominal aortic aneurysm via LYPD3 and GRIA4. Life Sci. 2020;253:117533.

    Not in our library10.1016/j.lfs.2020.117533

  193. 193.

    Zhang Y, Liu Z, Zhou M, Liu C. MicroRNA‐129‐5p inhibits vascular smooth muscle cell proliferation by targeting Wnt5a. Exp Ther Med. 2016;12(4):2651‐2656.

    Not in our library10.3892/etm.2016.3672

  194. 194.

    Zhao L, Ouyang Y, Bai Y, Gong J, Liao H. miR‐155‐5p inhibits the viability of vascular smooth muscle cell via targeting FOS and ZIC3 to promote aneurysm formation. Eur J Pharmacol. 2019;853:145‐152.

    Not in our library10.1016/j.ejphar.2019.03.030

  195. 195.

    Liang B, Che J, Zhao H, Zhang Z, Shi G. MiR‐195 promotes abdominal aortic aneurysm media remodeling by targeting Smad3. Cardiovasc Ther. 2017;35(6):e12286.

    Not in our library10.1111/1755-5922.12286

  196. 196.

    Cao X, Cai Z, Liu J, et al. miRNA504 inhibits p53 dependent vascular smooth muscle cell apoptosis and may prevent aneurysm formation. Mol Med Rep. 2017;16(3):2570‐2578.

    Not in our library10.3892/mmr.2017.6873

  197. 197.

    Zhang Z, Liang K, Zou G, et al. Inhibition of miR‐155 attenuates abdominal aortic aneurysm in mice by regulating macrophage‐mediated inflammation. Biosci Rep. 2018;38(3).

    Not in our library10.1042/bsr20171432

  198. 198.

    Ma X, Yao H, Yang Y, et al. miR‐195 suppresses abdominal aortic aneurysm through the TNF‐alpha/NF‐kappaB and VEGF/PI3K/Akt pathway. Int J Mol Med. 2018;41(4):2350‐2358.

    Not in our library10.3892/ijmm.2018.3426

  199. 199.

    Chan CY, Chan YC, Cheuk BL, Cheng SW. Clearance of matrix metalloproteinase‐9 is dependent on low‐density lipoprotein receptor‐related protein‐1 expression downregulated by microRNA‐205 in human abdominal aortic aneurysm. J Vasc Surg. 2017;65(2):509‐520.

    Not in our library10.1016/j.jvs.2015.10.065

  200. 200.

    Chan CYT, Cheuk BLY, Cheng SWK. Abdominal aortic aneurysm‐associated MicroRNA‐516a‐5p regulates expressions of methylenetetrahydrofolate reductase, matrix metalloproteinase‐2, and tissue inhibitor of matrix metalloproteinase‐1 in human abdominal aortic vascular smooth muscle cells. Ann Vasc Surg. 2017;42:263‐273.

    Not in our library10.1016/j.avsg.2016.10.062

  201. 201.
    miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development · 2014
    Corrected
  202. 202.

    Nakao T, Horie T, Baba O, et al. Genetic ablation of MicroRNA‐33 attenuates inflammation and abdominal aortic aneurysm formation via several anti‐inflammatory pathways. Arterioscler Thromb Vasc Biol. 2017;37(11):2161‐2170.

    Not in our library10.1161/atvbaha.117.309768

  203. 203.

    Pei H, Tian C, Sun X, et al. Overexpression of MicroRNA‐145 promotes ascending aortic aneurysm media remodeling through TGF‐beta1. Eur J Vasc Endovasc Surg. 2015;49(1):52‐59.

    Not in our library10.1016/j.ejvs.2014.10.018

  204. 204.

    Yang P, Wu P, Liu X, et al. MiR‐26b suppresses the development of stanford type A aortic dissection by regulating HMGA2 and TGF‐beta/Smad3 signaling pathway. Ann Thorac Cardiovasc Surg. 2020;26(3):140‐150.

    Not in our library10.5761/atcs.oa.19-00184

  205. 205.

    Huang W, Huang C, Ding H, et al. Involvement of miR‐145 in the development of aortic dissection via inducing proliferation, migration, and apoptosis of vascular smooth muscle cells. J Clin Lab Anal. 2020;34(1):e23028.

    Not in our library10.1002/jcla.23028

  206. 206.

    Li T, Liu C, Liu L, et al. Regulatory mechanism of MicroRNA‐145 in the pathogenesis of acute aortic dissection. Yonsei Med J. 2019;60(4):352‐359.

    Not in our library10.3349/ymj.2019.60.4.352

  207. 207.

    Shen H, Lu S, Dong L, et al. hsa‐miR‐320d and hsa‐miR‐582, miRNA biomarkers of aortic dissection, regulate apoptosis of vascular smooth muscle cells. J Cardiovasc Pharmacol. 2018;71(5):275‐282.

    Not in our library10.1097/fjc.0000000000000568

  208. 208.

    Tang Y, Yu S, Liu Y, Zhang J, Han L, Xu Z. MicroRNA‐124 controls human vascular smooth muscle cell phenotypic switch via Sp1. Am J Physiol Heart Circ Physiol. 2017;313(3):H641‐h649.

    Not in our library10.1152/ajpheart.00660.2016

  209. 209.

    Wang Y, Dong CQ, Peng GY, et al. MicroRNA‐134‐5p regulates media degeneration through inhibiting VSMC phenotypic switch and migration in thoracic aortic dissection. Mol Ther Nucleic Acids. 2019;16:284‐294.

    Not in our library10.1016/j.omtn.2019.02.021

  210. 210.

    Zhang M, Wang Z. Downregulation of miR143/145 gene cluster expression promotes the aortic media degeneration process via the TGF‐beta1 signaling pathway. Am J Transl Res. 2019;11(1):370‐378.

    Not in our library

  211. 211.

    Sun Y, Xiao Y, Sun H, et al. miR‐27a regulates vascular remodeling by targeting endothelial cells’ apoptosis and interaction with vascular smooth muscle cells in aortic dissection. Theranostics. 2019;9(25):7961‐7975.

    Not in our library10.7150/thno.35737

  212. 212.

    Ma RW, Wang JY, Wu XJ, et al. Diagnostic value of miR‐133 in aortic dissection and its mechanism. Int J Clin Exp Pathol. 2017;10(3):2804‐2813.

    Not in our library

  213. 213.

    Xue L, Luo S, Ding H, et al. Upregulation of miR‐146a‐5p is associated with increased proliferation and migration of vascular smooth muscle cells in aortic dissection. J Clin Lab Anal. 2019;33(4):e22843.

    Not in our library10.1002/jcla.22843

  214. 214.

    Yu Y, Shi E, Gu T, et al. Overexpression of microRNA‐30a contributes to the development of aortic dissection by targeting lysyl oxidase. J Thorac Cardiovasc Surg. 2017;154(6):1862‐1869.

    Not in our library10.1016/j.jtcvs.2017.06.019

  215. 215.

    Huang X, Yue Z, Wu J, et al. MicroRNA‐21 knockout exacerbates angiotensin II‐induced thoracic aortic aneurysm and dissection in mice with abnormal transforming growth factor‐beta‐SMAD3 signaling. Arterioscler Thromb Vasc Biol. 2018;38(5):1086‐1101.

    Not in our library10.1161/atvbaha.117.310694

  216. 216.

    Cai B, Yang B, Huang D, et al. STAT3‐induced up‐regulation of lncRNA NEAT1 as a ceRNA facilitates abdominal aortic aneurysm formation by elevating TULP3. Biosci Rep. 2020;40(1).

    Not in our library10.1042/bsr20193299

  217. 217.

    He X, Wang S, Li M, et al. Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis. Theranostics. 2019;9(19):5558‐5576.

    Not in our library10.7150/thno.34463

  218. 218.

    Li DY, Busch A, Jin H, et al. H19 induces abdominal aortic aneurysm development and progression. Circulation. 2018;138(15):1551‐1568.

    Not in our library10.1161/circulationaha.117.032184

  219. 219.

    Zhang Z, Zou G, Chen X, et al. Knockdown of lncRNA PVT1 inhibits vascular smooth muscle cell apoptosis and extracellular matrix disruption in a murine abdominal aortic aneurysm model. Mol Cells. 2019;42(3):218‐227.

    Not in our library10.14348/molcells.2018.0162

  220. 220.

    Xia Q, Zhang L, Yan H, Yu L, Shan W, Jiang H. LUCAT1 contributes to MYRF‐dependent smooth muscle cell apoptosis and may facilitate aneurysm formation via the sequestration of miR‐199a‐5p. Cell Biol Int. 2020;44(3):755‐763.

    Not in our library10.1002/cbin.11270

  221. 221.

    Tian Z, Sun Y, Sun X, Wang J, Jiang T. LINC00473 inhibits vascular smooth muscle cell viability to promote aneurysm formation via miR‐212‐5p/BASP1 axis. Eur J Pharmacol. 2020;873:172935.

    Not in our library10.1016/j.ejphar.2020.172935

  222. 222.

    Huang B, Lu S, Lai H, Li J, Sun Y, Wang C. LncRNA LOXL1‐AS is up‐regulated in thoracic aortic aneurysm and regulated proliferation and apoptosis of aortic smooth muscle cells. Biosci Rep. 2019;39(9).

    Not in our library10.1042/bsr20191649

  223. 223.

    Chen S, Chen H, Yu C, et al. Long noncoding RNA myocardial infarction associated transcript promotes the development of thoracic aortic by targeting microRNA‐145 via the PI3K/Akt signaling pathway. J Cell Biochem. 2019;120(9):14405‐14413.

    Not in our library10.1002/jcb.28695

  224. 224.

    Guo X, Chang Q, Pei H, et al. Long non‐coding RNA‐mRNA correlation analysis reveals the potential role of HOTAIR in pathogenesis of sporadic thoracic aortic aneurysm. Eur J Vasc Endovasc Surg. 2017;54(3):303‐314.

    Not in our library10.1016/j.ejvs.2017.06.010

  225. 225.

    Wang S, Zhang X, Yuan Y, et al. BRG1 expression is increased in thoracic aortic aneurysms and regulates proliferation and apoptosis of vascular smooth muscle cells through the long non‐coding RNA HIF1A‐AS1 in vitro. Eur J Cardiothorac Surg. 2015;47(3):439‐446.

    Not in our library10.1093/ejcts/ezu215

  226. 226.

    Hu W, Wang Z, Li Q, Wang J, Li L, Jiang G. Upregulation of lincRNA‐p21 in thoracic aortic aneurysms is involved in the regulation of proliferation and apoptosis of vascular smooth muscle cells by activating TGF‐beta1 signaling pathway. J Cell Biochem. 2019;120(3):4113‐4120.

    Not in our library10.1002/jcb.27696

  227. 227.

    Allaire E, Muscatelli‐Groux B, Mandet C, et al. Paracrine effect of vascular smooth muscle cells in the prevention of aortic aneurysm formation. J Vasc Surg. 2002;36(5):1018‐1026.

    Not in our library10.1067/mva.2002.127347

  228. 228.

    Allaire E, Muscatelli‐Groux B, Guinault AM, et al. Vascular smooth muscle cell endovascular therapy stabilizes already developed aneurysms in a model of aortic injury elicited by inflammation and proteolysis. Ann Surg. 2004;239(3):417‐427.

    Not in our library10.1097/01.sla.0000114131.79899.82

  229. 229.

    Petrinec D, Liao S, Holmes DR, Reilly JM, Parks WC, Thompson RW. Doxycycline inhibition of aneurysmal degeneration in an elastase‐induced rat model of abdominal aortic aneurysm: Preservation of aortic elastin associated with suppressed production of 92 kD gelatinase. J Vasc Surg. 1996;23(2):336‐346.

    Not in our library10.1016/s0741-5214(96)70279-3

  230. 230.

    Xiong W, Knispel RA, Dietz HC, Ramirez F, Baxter T. Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome. J Vasc Surg. 2008;47(1):166‐172.

    Not in our library10.1016/j.jvs.2007.09.016

  231. 231.

    Meijer CA, Stijnen T, Wasser MNJM, Hamming JF, van Bockel JH, Lindeman JHN. Doxycycline for stabilization of abdominal aortic aneurysms. A randomized trial. Ann Intern Med. 2013;159:815‐823.

    Not in our library10.7326/0003-4819-159-12-201312170-00007

  232. 232.

    Baxter BT, Matsumura J, Curci JA, et al. Effect of doxycycline on aneurysm growth among patients with small infrarenal abdominal aortic aneurysms: a randomized clinical trial. JAMA. 2020;323(20):2029‐2038.

    Not in our library10.1001/jama.2020.5230

  233. 233.

    Allaire E, Forough R, Clowes M, Starcher B, Clowes AW. Local overexpression of TIMP‐1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest. 1998;102(7):1413‐1420.

    Not in our library10.1172/jci2909

  234. 234.

    Li Y, Lu G, Sun D, Zuo H, Wang DW, Yan J. Inhibition of endoplasmic reticulum stress signaling pathway: a new mechanism of statins to suppress the development of abdominal aortic aneurysm. PLoS One. 2017;12(4):e0174821.

    Not in our library10.1371/journal.pone.0174821

  235. 235.

    Schouten O, van Laanen JH, Boersma E, et al. Statins are associated with a reduced infrarenal abdominal aortic aneurysm growth. Eur J Vasc Endovasc Surg. 2006;32(1):21‐26.

    Not in our library10.1016/j.ejvs.2005.12.024

  236. 236.

    Bernardo BC, Ooi JY, Lin RC, McMullen JR. miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart. Future Med Chem. 2015;7(13):1771‐1792.

    Not in our library10.4155/fmc.15.107

  237. 237.

    Jalalzadeh H, Indrakusuma R, Blankensteijn JD, et al. Design and protocol of a comprehensive multicentre biobank for abdominal aortic aneurysms. BMJ Open. 2019;9(8):e028858.

    Not in our library10.1136/bmjopen-2018-028858

  238. 238.

    Wills A, Thompson MM, Crowther M, et al. Elastase‐induced matrix degradation in arterial organ cultures: an in vitro model of aneurysmal disease. J Vasc Surg. 1996;24(4):667‐679.

    Not in our library10.1016/s0741-5214(96)70083-6

  239. 239.

    Bogunovic N, Meekel JP, Majolee J, et al. Patient‐specific 3‐dimensional model of smooth muscle cell and extracellular matrix dysfunction for the study of aortic aneurysms. J Endovasc Ther. 2021;28(4):604‐613.

    Not in our library10.1177/15266028211009272

  240. 240.

    Yokoyama U, Tonooka Y, Koretake R, et al. Arterial graft with elastic layer structure grown from cells. Sci Rep. 2017;7(1):140.

    Not in our library10.1038/s41598-017-00237-1

  241. 241.

    Burger J, Bogunovic N, de Wagenaar NP, et al. Molecular phenotyping and functional assessment of smooth muscle like‐cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1. Hum Mol Genet. 2021.

    Not in our library10.1093/hmg/ddab190

  242. 242.

    van de Pol V, Kurakula K, DeRuiter MC, Goumans MJ. Thoracic aortic aneurysm development in patients with bicuspid aortic valve: what is the role of endothelial cells? Front Physiol. 2017;8:938.

    Not in our library10.3389/fphys.2017.00938

  243. 243.

    Ramella M, Boccafoschi F, Bellofatto K, et al. Endothelial MMP‐9 drives the inflammatory response in abdominal aortic aneurysm (AAA). Am J Transl Res. 2017;9(12):5485‐5495.

    Not in our library

  244. 244.

    Sun J, Deng H, Zhou Z, Xiong X, Gao L. Endothelium as a potential target for treatment of abdominal aortic aneurysm. Oxid Med Cell Longev. 2018;2018:1‐12.

    Not in our library10.1155/2018/6306542

Cited by papers we hold 1

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.