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Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation

Anny-Claude Luissint, Cédric Artus, Fabienne Glacial and 2 more

Fluids and Barriers of the CNS · 2012 · Review

doi:10.1186/2045-8118-9-23

Abstract

The Blood–brain barrier (BBB), present at the level of the endothelium of cerebral blood vessels, selectively restricts the blood-to-brain paracellular diffusion of compounds; it is mandatory for cerebral homeostasis and proper neuronal function. The barrier properties of these specialized endothelial cells notably depend on tight junctions (TJs) between adjacent cells: TJs are dynamic structures consisting of a number of transmembrane and membrane-associated cytoplasmic proteins, which are assembled in a multimolecular complex and acting as a platform for intracellular signaling. Although the structural composition of these complexes has been well described in the recent years, our knowledge about their functional regulation still remains fragmentary. Importantly, pericytes, embedded in the vascular basement membrane, and perivascular microglial cells, astrocytes and neurons contribute to the regulation of endothelial TJs and BBB function, altogether constituting the so-called neurovascular unit. The present review summarizes our current understanding of the structure and functional regulation of endothelial TJs at the BBB. Accumulating evidence points to a correlation between BBB dysfunction, alteration of TJ complexes and progression of a variety of CNS diseases, such as stroke, multiple sclerosis and brain tumors, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. Understanding how TJ integrity is controlled may thus help improve drug delivery across the BBB and the design of therapeutic strategies for neurological disorders.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

The BBB maintains the homeostasis of the central nervous system (CNS) by (i) strictly limiting the passive diffusion of polar substances from the blood to the brain, (ii) mediating the transport of nutrients to the brain parenchyma as well as the efflux from the brain of toxic metabolites and xenobiotics, (iii) regulating the migration of circulating immune cells. Formed by specialized vascular endothelial cells, the BBB is tightly controlled by pericytes, embedded in the vascular basement membrane, perivascular microglial cells, astrocytes and neurons which altogether constitute the neurovascular unit (NVU), a concept highlighting the functional cell-cell interactions supporting BBB function.

BBB endothelial cells display a unique phenotype characterized by the presence of TJs and the expression of specific polarized transport systems. TJs constitute the most apical intercellular junctional complex in polarized epithelium and endothelium, with three key biological functions: a barrier to paracellular diffusion of blood-borne polar substances, a fence preventing the lateral diffusion of lipids and integral membrane proteins, thus maintaining cell polarization and an intracellular signaling platform which will be described below.

Brain endothelial TJ strands, like epithelial TJs, are composed of integral membrane proteins (occludin, claudins and junctional adhesion molecules (JAMs)) involved in intercellular contacts and interactions with cytoplasmic scaffolding proteins such as zonula occludens (ZO) proteins, actin cytoskeleton and associated proteins, such as protein kinases, small GTPases and heterotrimeric G-proteins.

Excellent reviews have recently been published on the architecture of TJ complexes in epithelial and brain endothelial cells. Here we will briefly recall the main features of the structural organization of TJs at the BBB and will focus on transcriptional regulation, post-translational modifications and subcellular localization of TJ proteins and their consequences for BBB integrity with exposure to various environmental stimuli and during CNS disorders.

Components of TJs in brain endothelial cells

As in polarized epithelial cells where TJs have been mostly studied, the TJ backbone in brain endothelial cells consists of transmembrane proteins (occludin, claudins and JAMs) which recruit a number of membrane-associated cytoplasmic proteins.

Transmembrane proteins as the BBB TJ backbone

Occludin (60kDa), a tetraspan integral membrane protein, was the first TJ-specific protein identified in epithelial cells and shown to be functionally important for barrier function. It is a member of the family of TJ-associated marvel proteins (TAMP) with tricellulin (marvelD2) and marvelD3. Both the MARVEL transmembrane domain of occludin, encompassing the four transmembrane helices, and its coiled coil cytosolic C-terminus were recently described to mediate its lateral (i.e. cis-) oligomerization in epithelial MDCK cells. More precisely, cystein residues in these domains are directly involved in oligomerization through disulfide bridge formation. This process being redox-sensitive, oligomerization of occludin likely contributes to the redox-dependency of the TJ assembly: whereas normoxia conditions support occludin oligomerization and contribute to TJ assembly, oxidative stress associated with hypoxia-reoxygenation or inflammation results in TJ disruption. This novel concept that occludin plays a key role in the redox regulation of TJs has been very recently reviewed.

In addition, the second extracellular domain of occludin is required for its stable assembly in TJs. Indeed, synthetic peptides corresponding to this domain were shown to perturb TJ permeability barrier in epithelial cells. The important contribution of occludin to TJ function is illustrated by the observations that ectopic expression of chicken occludin induced the formation of TJ-like structures in Sf9 insect cells, while increasing electrical resistance in MDCK cells. Conversely, occludin degradation induced by viruses or bacteria (like HIV-1 Tat protein or Neisseria meningitidis), is associated with increased permeability in primary or immortalized human brain microvascular endothelial cells, respectively. However, well-developed TJ strands were reported in cells lacking occludin (human or guinea pig testis) and between adjacent occludin-deficient epithelial cells; together with the report that occludin deficient-mice are viable, exhibiting normal TJs morphology as well as intestinal epithelium barrier function, these observations indicate that occludin is dispensable for TJ formation.

Claudins constitute a large family of 20-27kDa membrane proteins (with four transmembrane domains) expressed in TJs in various cell types (endothelial and epithelial cells). Brain endothelial cells predominantly express claudin-3 and claudin-5, claudin-12 likely being also expressed. A large corpus of data clearly establishes the key contribution of claudin-3 and claudin-5 to TJ formation and integrity at the BBB. Indeed, exogenous expression of claudin-5 strengthens barrier properties in cultured rat brain endothelial cells, whereas depletion of claudin-5 induces the disruption of the BBB in genetically-altered mice and in cultured human brain endothelial cells. Claudins support TJ integrity via their capacity of cis- and trans-homodimerization as well as heterodimerization, notably through their second extracellular loop, as recently reported for claudin-5. Claudin-5 can interact with claudin-3 and the selective loss of the latter during autoimmune encephalomyelitis or human glioblastoma is associated with BBB breakdown.

Beside occludin and claudins, JAMs, although not essential to TJ formation in epithelial and endothelial cells, may be involved in the facilitation of assembly of TJ components and in the establishment of cell polarity by recruiting the polarity complex (Par-3/Par-6/aPKC: see below) to TJs.

Membrane-associated cytoplasmic proteins in BBB TJs

A number of cytoplasmic proteins have been described to associate with TJ transmembrane proteins and to contribute somehow to TJ integrity in epithelial and brain endothelial cells. Among them, the PDZ domain-containing, membrane-associated guanylate kinase (MAGUK) family members have been largely documented: zonula occludens-1 (ZO-1, 225kDa), ZO-2 (160kDa), and ZO-3 (130kDa). ZO-1 forms heterodimers with ZO-2 and ZO-3. ZO proteins interact with the C-terminal domain of claudins via their first PDZ domain (PDZ1), to JAMs by the third PDZ domain (PDZ3) and to occludin via their GUK domains. It is well established that ZO proteins are essential to the assembly of claudins, occludin and JAM-A at TJs, then anchoring this multimolecular complex to the actin cytoskeleton. Par-3 (also known as ASIP) binds to JAM proteins and recruits to TJs atypical protein kinase C and Par-6, the three proteins then forming a Planar Cell Polarity (PCP) complex in polarized epithelial cells. Only very recently was their expression confirmed also in brain endothelial cells.

Among additional TJ-associated proteins, heterotrimeric G-proteins (Gαi) were first described, in association with ZO-1, to contribute to TJ biogenesis and maintenance in epithelial and brain endothelial cells. Gαi2 proteins were reported to be involved in T-lymphocyte extravasation, including in brain. More recently, we reported that Gαi2 interacts with claudin-5 and that its depletion increases brain endothelial cell permeability in vitro and delays TJ reassembly after hyperosmotic shock (induced by a high concentration mannitol treatment). On the basis of these observations, we proposed that claudin-5 and Gαi2, whether they interact directly or indirectly, might control TJ integrity as components of a multiprotein complex, including caveolin, ZO-1 linked to the actin cytoskeleton and possibly also, occludin and MUPP-1.

Developmental role of astrocyte and pericyte secreted proteins

Development and maintenance of the BBB requires functional interactions between endothelial cells and perivascular cells of the NVU: whereas astrocytes have been well documented to regulate BBB formation and integrity, only recently was the role of pericytes unraveled (for reviews:).

Indeed, early studies using co-culture of cerebral endothelial cells and astrocytes (or culture in the presence of astrocyte-conditioned medium) highlighted the role of astrocyte-derived soluble factors in maintaining the specialized phenotype of brain endothelial cells (Figure 1). In addition, more recent reports established that pericytes also actively contribute to BBB formation during development by the release of several growth factors and morphogens.

Astrocyte- and pericyte-derived Wnt and hedgehog morphogens were reported to control BBB formation during development and TJ integrity. Indeed, the Wnt/β-catenin pathway has been recently discovered as a major BBB-regulating pathway. Wnt ligation to its membrane receptors, Frizzled4 (Fz4) and LRP5/6 expressed by brain endothelial cells, inhibits the β-catenin repressor complex, allowing β-catenin cytoplasmic accumulation, nuclear translocation and transcription of various genes, including claudin-3 in cultured murine brain endothelial cells (Figure 1). Moreover, in vivo inactivation of Wnt factors (Wnt7a and Wnt7b), Fz4 receptor or injection of a soluble inhibitor of the Wnt/ Frizzled receptor interaction lead to major vascular defects in the CNS (interestingly, not in non-neuronal tissues) and to BBB breakdown, clearly demonstrating a specific role for the Wnt/β-catenin pathway in BBB differentiation during development and for BBB maintenance in adulthood. These exciting observations (for review, see:) open new research avenues for controlling BBB permeability in pathological situations as well as improving drug delivery to the CNS.

Sonic hedgehog (Shh), another well-known morphogen protein, acting through its membrane receptors Patched-1 (Ptch1)/Smoothened (Smo), was also recently shown to control BBB differentiation and to maintain the immune privilege of the CNS by inhibiting the endothelial production of chemokines and expression of adhesion proteins supporting extravasation of leukocytes to the brain.

In conclusion, these recent findings further document, at the molecular and cellular levels, the functional interactions between brain endothelial cells, pericytes and astrocytes and emphasise the key importance of the NVU in controlling BBB permeability and integrity. The major cellular cross-talks at the NVU are illustrated in Figure 1.

Role of basement membrane-associated proteins

The vascular basement membrane (or basal lamina) is a complex structure, composed of four glycoprotein families: laminins, collagen type IV, nidogens and heparan sulfate proteoglycans. Recent studies have unraveled the contribution of the endothelial laminin isoform α5 to the barrier property of the BBB by selectively inhibiting lymphocyte infiltration; the basement membrane thus contributes to maintain the well-known “immune privilege” of the CNS.

The heparan sulfate proteoglycan agrin is found in the basal lamina of brain microvessels. A strict positive correlation has been reported between agrin deposition and expression of occludin, whereas, conversely, absence of agrin in glioblastoma vessels was shown to correlate with the lack of TJ proteins (occludin, claudin-5): these observations strongly suggest that agrin may regulate TJ formation in brain endothelium. Recently, agrin was described to be involved in the development of the BBB by contributing to astrocyte polarity. Moreover, β1-integrin-mediated attachment of brain endothelial cells to the basement membrane has also been reported to be critical for stabilizing claudin-5 localization at TJs and maintaining BBB integrity in vitro and in vivo. Genetic deletion of β1-integrin decreases the expression of the polarity protein Par-3, leading to the loss of endothelial cell polarity: these recent data suggest that β1-integrin-mediated brain endothelial cell adhesion to the basement membrane may lead to the development of cell polarity, TJ formation and BBB integrity.

VE-cadherin and β-catenin as modulators of TJs

In addition to TJs, junctional complexes between endothelial cells include adherens junctions (AJs), constituted by transmembrane proteins VE-cadherin linked to the actin cytoskeleton through catenins (eg: p120-catenin, α- and β-catenin). Interestingly, AJ and TJ complexes functionally interact in brain endothelial cells: indeed, VE-cadherin engagement induces claudin-5 transcription through inhibition of FoxO1 activity (a transcription repressor of claudin-5 gene) and β-catenin sequestration (a stabilizer of FoxO1 activity) in AJ complexes, in line with the above-mentioned capacity of β-catenin, downstream of Wnt receptor activation, to control claudin gene expression. These findings clearly place VE-cadherin upstream of claudin-5 in the establishment, maturation and maintenance of endothelial cell-cell junctions.

Contribution of shear stress to TJ modulation and BBB integrity

It is established that one important mechanical stimulus contributing to BBB formation and maintenance is shear stress, a tangential force generated by flow across the apical surface of vascular endothelium. In line with the accepted concept that cerebral microcirculation is highly heterogeneous, mean shear stress levels in brain microvessels has been estimated in a range as wide as 0.01 to 10 dynes/cm2 in capillaries and 10–100 dynes/cm2 in arterioles. Several dynamic in vitro models were developed in order to mimic a physiological situation (using laminar, steady flow) or a pathological condition (such as atherosclerosis), using an irregular flow. Interestingly, culturing human umbilical vein endothelial cells (HUVECs) in a laminar flow chamber in the presence of meningococci (N. meningitidis) was instrumental for unraveling some key molecular mechanisms of CNS invasion by these meningitis-causing human pathogens. Regarding BBB differentiation, culture of brain endothelial cells under flow has been reported to induce the expression of the TJ proteins occludin and ZO-1, to promote actin cytoskeleton reorganization and to reduce endothelial permeability. In addition, very recent findings suggest that physiological shear stress (6 dynes/cm2) may increase the expression of a variety of BBB-associated genes in human brain microvascular endothelial cells, such as genes encoding for TJ proteins (ZO1, claudin-3, claudin-5), several influx transporters (Glut-1) and multidrug resistance efflux transporters (ABCB1/P-gp, ABCC5/MRP5). Nevertheless, further investigation is still required to get a better understanding of the contribution of shear stress to the maintenance of BBB integrity.

Dysregulation of the BBB via phosphorylation and relocalization of TJ proteins

Studies on CNS diseases associated with BBB dysfunctions (e.g. stroke, multiple sclerosis, cerebral infection, brain tumors, Parkinson’s and Alzheimer’s diseases) have pointed to various molecular mechanisms involved in disruption of TJ integrity, notably including Serine/Threonine (Ser/Thr)- and Tyrosine (Tyr)-phosphorylation, down-regulation, degradation or translocation of TJ proteins; a non exhaustive list of related reports are presented in Table 1. More than other TJ proteins (such as claudins or JAMs), occludin has been the focus of numerous studies investigating post-translational modifications and their consequences on TJ integrity (see for review:).

Ser/Thr-phosphorylation of TJ proteins and regulation of barrier permeability

Ser/Thr-phosphorylation forms of occludin are found concentrated at TJs whereas dephosphorylated occludin is rather detected on basolateral membranes and associated with disrupted TJs in epithelial cells as well as in brain endothelial cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis characterized by brain inflammation. Regarding claudin-5, phosphorylation of its C-terminal domain on Thr207 residue in response to PKA or Rho kinase activation generally affected TJ integrity in brain endothelial cells and increased permeability.

Differential regulation of TJs by Protein Kinases C (PKCs)

PKC-dependent pathways have been involved in endothelial barrier disruption, as reported following treatment by pertussis toxin, an inhibitor of Gαi heterotrimeric G proteins, or in response to the pro-inflammatory cytokine interleukin-6 (IL-6) which plays a critical role during hypoxia. However, early reports had clearly established that PKC activity was crucial for BBB integrity in epithelial cells, inasmuch as PKC inhibitors completely blocked the formation of TJs; in addition, PKC-mediated phosphorylation of occludin (on residue Ser338) was involved in occludin targeting to TJs and TJ stabilization in epithelial MDCK cells.

At least part of the interpretation of these apparently conflicting data may be found in the heterogeneity of the PKC family. The Ser/Thr-kinases PKCs are indeed classified into conventional (cPKC: α, βI, βII and γ), novel (nPKC: δ, ε, θ, η, μ) and atypical (aPKC: λ,ζ) PKC isozymes according to their modes of regulation. Accumulating evidence has pointed to a differential capacity of PKC isozymes to regulate BBB permeability. Indeed, activation of nPKC-θ and aPKC-ζ signaling by hypoxia-mediated TJ proteins results in relocalization (such as claudin-5, occludin, ZO-1) and increased BBB permeability in rat brain microvascular endothelial cells (in vitro and in vivo). In human brain microvascular endothelial cells, cPKCα, cPKC βII and aPKCλ/ζ isoforms were activated by HIV-1 gp120 envelope protein, leading to BBB disruption, intracellular calcium increase and monocyte migration across cell monolayer. Interestingly, when cPKC-α was found to contribute to TJ disassembly, nPKC-ε activation mediated TJ formation in epithelial MDCK cells. In line with this observation, over-expression of cPKC-α in rat epididymal microvascular endothelial cells was reported to enhance thrombin-induced permeability, whereas nPKC-δ expression promoted barrier function. By contrast, IL-25, expressed by mouse brain capillary endothelial cells, was shown to prevent inflammation-induced BBB disruption and down-regulation of TJ proteins (occludin, claudin-5, JAMs) through activation of the nPKC-ε pathway. Altogether, these observations strongly suggest that nPKC-selective activation generally contributes to maintaining barrier integrity, whereas cPKC activation has the opposite effect, both in polarized epithelium and endothelium (Table 1).

Regarding aPKC isoforms (λ and ζ), they have been shown to contribute to the establishment of epithelial cell polarity, via participation in the PCP complex together with Par-3 and Par-6. As mentioned above, the PCP complex is recruited to endothelial TJs by Par-3 binding to JAM proteins. Over-expression of a dominant negative mutant of aPKC causes mislocalization of Par-3 and affects the biogenesis of the TJs in epithelial cells, suggesting that Par-3 is a substrate of aPKC and that its localization in epithelial cells is dependent upon its phosphorylation. In the same line, the VE-cadherin/CCM1 (a protein encoded by the CCM1 gene which is mutated in a large proportion of patients affected by cerebral cavernous malformation) complex controls aPKC-ζ activation and Par-3 localization during early steps of brain endothelial cell polarization. The participation of this PCP complex to TJ integrity was further illustrated by the recent observation that meningococcal adhesion to human cerebral endothelial cells recruited Par-3, Par-6 and aPKC-ζ under bacterial colonies and induced disruption of cell-cell junctions. Surprisingly, a distinct Par-3/Par-6 complex, directly associated with VE-cadherin and lacking aPKC, has also been identified in endothelial cells. Finally, although additional polarity complexes are known in epithelial cells (the apical Crumbs complex and the basolateral Scribble complex) where they also contribute to TJ formation and regulation, no similar observations have been reported, to our knowledge, in brain endothelial cells.

BBB disruption mediated by Rho/ Rho kinase and MLCK activation

The RhoA GTPase signaling pathway, activated by several membrane receptors, has been extensively documented in various cell types to induce actin cytoskeleton rearrangements involved in cell migration and proliferation. In brain endothelial cells, RhoA activation increased permeability, in response to inflammatory stimuli, through one of its major effectors Rho kinase (ROCK). Among these inflammatory stimuli, chemokines like MCP-1/CCL2, acting via their seven transmembrane-domain receptors, are known to activate the RhoA/ROCK pathway in mouse brain endothelial cells, to induce occludin, claudin-5 and ZO-1 Ser/Thr-phosphorylation, followed by their delocalization from TJs, ultimately leading to increased barrier permeability. Similarly, enhanced monocyte migration across human brain endothelial cells was observed in an HIV-1 encephalitis model. Also, adhesion molecules like ICAM-1 and VCAM-1 were shown, in response to lymphocyte/monocyte adhesion, to transduce signals in rat brain endothelial cell lines including activation of the RhoA/ ROCK pathway: activation of this pathway ultimately leads to enhanced lymphocyte migration, suggesting that this process may be involved in the massive infiltration of immune cells into the CNS observed in multiple sclerosis. It must be mentioned, however, that lymphocyte migration across the BBB may also happen via a transcellular pathway, leaving intact endothelial TJs.

Rearrangements of the actin cytoskeleton have long been recognized to be regulated, not only by the RhoA/ROCK pathway, but also, often in a coordinated manner, by the myosin light chain kinase (MLCK): MLCK directly phosphorylates the myosin light chain, leading to actomyosin contraction and endothelial barrier disruption. In the same line, inhibition of MLCK in bovine brain endothelial cells was more recently reported to prevent hypoxia-induced BBB disruption, whereas alcohol increased human brain endothelial cell permeability via activation of MLCK and phosphorylation of occludin and claudin-5. Recently, pro-inflammatory cytokines (IL1β and TNFα), secreted by lymphocytes chronically infected by the HTLV-1 retrovirus, were reported to induce barrier disruption in the human brain endothelial cell line hCMEC/D3, associated with loss of occludin and ZO-1 through activation of the MLCK pathway.

In conclusion, as summarized in Table 1, inflammation- or infection-induced actin cytoskeleton rearrangements in brain endothelial cells, mediated by the RhoA/ROCK and/or MLCK pathways, are associated with the phosphorylation, followed by delocalization or degradation of TJ proteins, and BBB disruption.

BBB dysregulation by Tyr-phosphorylation of TJ proteins

Early studies with cultured bovine brain endothelial cells and MDCK cells had pointed to Tyr-phosphorylation as a mechanism for increasing TJ permeability. Accumulating evidence demonstrated that Tyr-phosphorylation of TJ proteins, as well as AJ proteins, was directly involved in BBB disruption, as observed in various pathological situations, although the identity of the Tyr-kinases involved often remained unknown. Unlike occludin Ser/Thr phosphorylation associated with barrier formation, as mentioned above, occludin Tyr-phosphorylation was reported to be associated with increased permeability of cultured rat brain endothelial cells exposed to glutamate, as a way to mimic cerebral ischemia (Table 1). Like other pro-inflammatory cytokines, transforming growth factor (TGF)-β1 is known to increase BBB permeability: as recently reported in bovine retinal and human brain endothelial cells, this effect was mediated by Tyr-phosphorylation of both claudin-5 and VE-cadherin. Vascular endothelial growth factor (VEGF), a major angiogenic factor, which is drastically enhanced in response to hypoxia, promotes Tyr-phosphorylation of TJ proteins (ZO-1, occludin) in mouse brain and retinal endothelial cells either directly via its membrane receptor tyrosine kinase VEGFR2 or via the activation of the cytosolic tyrosine kinase c-src. VEGF-mediated Tyr-phosphorylation of TJ proteins in brain endothelial cells was often followed by their down-regulation and/or re-localization, leading to TJ destabilization and permeability increase.

Alterations of expression and localization of TJ proteins

Caveolae are specialized plasma membrane microdomains, abundantly found in endothelial cells where they mediate various biological events such as transcytosis, vascular permeability and angiogenesis. They are enriched in the small membrane protein caveolin-1 which has been shown to recruit TJ proteins. Caveolae-mediated endocytosis induced by actin depolymerization was reported to evoke occludin internalization in MDCK cells. Interestingly, exposure of cultured rat brain endothelial cells to the HIV-1 Tat protein was reported to increase TJ permeability, through alterations in expression and distribution of TJs proteins: occludin, claudin-5, ZO1, ZO2. In the same line, the increase in TJ permeability observed in mouse brain endothelial cell response to the inflammatory cytokine CCL2 was recently shown to be associated with claudin-5 and occludin internalization in a caveolae-dependent manner. Altogether these results strongly support the conclusion that alterations in expression and localization of TJ proteins, associated or not with their phosphorylation in response to various pathological stimuli, directly contribute to TJ disruption and BBB permeability increase (Table 1); in addition, they suggest a role of caveolin-1/caveolae in such TJ remodeling.

Conclusion

The brain endothelial TJ complex, which constitutes a key feature of the BBB, is now understood as a scaffolding and signaling platform in close interaction with the actin cytoskeleton and the AJ complex. It also appears as a dynamic complex, submitted to post-translational modifications in response to physiological and pathological stimuli. Indeed, perivascular cells of the NVU, notably astrocytes and pericytes, secrete multiple growth factors and morphogens that contribute to TJ formation and integrity. Conversely, various pathological situations associated with the presence of inflammatory cytokines, reactive oxygen species or pathogens, lead to TJ disruption following phosphorylation and/or internalization of TJ proteins.

Although our understanding of TJ architecture and function has significantly increased over the last ten years, a number of issues will have to be addressed in the next future, in particular taking advantage of new and/or global analysis technologies. For example, super-resolution light microscopy (time-lapse stimulated emission depletion (STED) imaging) recently appeared as a very powerful approach to unravel synapse assembly and plasticity; in the same line, super-resolution microscopy of TJs (with a resolution down to 50–80 nm) of cerebral microvessels in brain slices should provide a more accurate understanding of TJ organization and dynamics. Also, thanks to the availability of validated BBB in vitro models, identification by mass spectrometry (MS/MS analysis) of the secreted proteins (so-called ‘secretome’) from brain endothelial co-cultures with astrocytes or pericytes may unravel new paracrine signaling pathways in the NVU which contribute to the stabilization of TJs at the BBB; in addition, similar analyses in the presence of inflammatory agents or pathogens may highlight unsuspected mechanisms of TJ disruption. This approach will complement quantitative targeted absolute proteomics (also known as selected reaction monitoring (SRM)), an emerging approach to quantify membrane proteins. This technology will also greatly benefit the field, allowing absolute quantification of TJ proteins in physiological and various pharmacological situations, as recently proposed. The treatment of neurological diseases is currently hampered by difficulties encountered in delivering therapeutic compounds to the brain, across the BBB. Because previous drug delivery strategies based on transcellular transport machinery have shown limited efficacy so far, it is tempting to propose that transient modulation of TJs at the BBB, using in vitro models of the BBB and in vivo models of human pathologies, may constitute an alternative approach for drug delivery to the brain. Clearly, this field will benefit greatly from an in-depth understanding of TJ architecture and functional regulatory mechanisms.

Abbreviations

AJ: Adherens junction; BBB: Blood brain barrier; CNS: Central nervous system; ECL: Extracellular loop; Fz: Frizzled; HUVEC: Human umbilical vein endothelial cell; IL: Interleukin; JAM: Junctional adhesion molecule; MAGUK: Membrane associated guanylate kinase; MLCK: Myosin light chain kinase; NVU: Neurovascular unit; PCP: Planar cell polarity; PKC: Protein kinase C; Ptch1: Patched-1; ROCK: Rho kinase; Shh: Sonic hedgehog; Smo: Smoothened; TAMP: Tight junction-associated marvel proteins; TGF: Transforming growth factor; TJ: Tight junction; VEGF: Vascular endothelial growth factor; ZO: Zonula occludens.

Competing interests

The authors declare no conflict of interest.

Authors’ contributions

ACL and CA: were responsible for the collection of data and references, and for the drafting of the document. FG and KG were involved in the collection of data and drafting of the document. POC was responsible for the drafting and editing of the document, and for the discussion of the data. All authors read and approved the final manuscript.

References 180

  1. 1.

    Abbott NJ Patabendige AA Dolman DE Yusof SR Begley DJ Structure and function of the blood–brain barrierNeurobiol Dis2010 371325

    Not in our library10.1016/j.nbd.2009.07.030

  2. 2.

    Begley DJ Brightman MW Structural and functional aspects of the blood–brain barrierProg Drug Res2003 613978

    Not in our library10.1007/978-3-0348-8049-7_2

  3. 3.

    Wolburg H Noell S Mack A Wolburg-Buchholz K Fallier-Becker P Brain endothelial cells and the glio-vascular complexCell Tissue Res2009 3357596

    Not in our library10.1007/s00441-008-0658-9

  4. 4.

    Tsukita S Furuse M Itoh M Multifunctional strands in tight junctionsNat Rev Mol Cell Biol2001 2285293

    Not in our library10.1038/35067088

  5. 5.

    Cereijido M Valdes J Shoshani L Contreras RG Role of tight junctions in establishing and maintaining cell polarityAnnu Rev Physiol1998 60161177

    Not in our library10.1146/annurev.physiol.60.1.161

  6. 6.

    Gumbiner BM Breaking through the tight junction barrierJ Cell Biol1993 12316311633

    Not in our library10.1083/jcb.123.6.1631

  7. 7.

    Schneeberger EE Lynch RD Structure, function, and regulation of cellular tight junctionsAm J Physiol1992 262L647661

    Not in our library10.1152/ajplung.1992.262.6.l647

  8. 8.

    Vorbrodt AW Dobrogowska DH Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist’s viewBrain Res Brain Res Rev2003 42221242

    Not in our library10.1016/s0165-0173(03)00177-2

  9. 9.

    Luissint AC Federici C Guillonneau F Chretien F Camoin L Glacial F Ganeshamoorthy K Couraud PO Guanine nucleotide-binding protein Galphai2: a new partner of claudin-5 that regulates tight junction integrity in human brain endothelial cellsJ Cereb Blood Flow Metab2012 32860873

    Not in our library10.1038/jcbfm.2011.202

  10. 10.

    Aijaz S Balda MS Matter K Tight junctions: molecular architecture and functionInt Rev Cytol2006 248261298

    Not in our library10.1016/s0074-7696(06)48005-0

  11. 11.
    Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences · 2011
    No notice
  12. 12.

    Ando-Akatsuka Y Saitou M Hirase T Kishi M Sakakibara A Itoh M Yonemura S Furuse M Tsukita S Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat-kangaroo homologuesJ Cell Biol1996 1334347

    Not in our library10.1083/jcb.133.1.43

  13. 13.

    Furuse M Hirase T Itoh M Nagafuchi A Yonemura S Tsukita S Occludin: a novel integral membrane protein localizing at tight junctionsJ Cell Biol1993 12317771788

    Not in our library10.1083/jcb.123.6.1777

  14. 14.

    Balda MS Whitney JA Flores C Gonzalez S Cereijido M Matter K Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane proteinJ Cell Biol1996 13410311049

    Not in our library10.1083/jcb.134.4.1031

  15. 15.

    Ikenouchi J Furuse M Furuse K Sasaki H Tsukita S Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cellsJ Cell Biol2005 171939945

    Not in our library10.1083/jcb.200510043

  16. 16.

    Raleigh DR Marchiando AM Zhang Y Shen L Sasaki H Wang Y Long M Turner JR Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functionsMol Biol Cell2010 2112001213

    Not in our library10.1091/mbc.e09-08-0734

  17. 17.
    Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family · 2009
    No notice
  18. 18.

    Yaffe Y Shepshelovitch J Nevo-Yassaf I Yeheskel A Shmerling H Kwiatek JM Gaus K Pasmanik-Chor M Hirschberg K The MARVEL transmembrane motif of occludin mediates oligomerization and targeting to the basolateral surface in epitheliaJ Cell Sci2012 12535453556

    Not in our library10.1242/jcs.100289

  19. 19.

    Blasig IE Winkler L Lassowski B Mueller SL Zuleger N Krause E Krause G Gast K Kolbe M Piontek J On the self-association potential of transmembrane tight junction proteinsCell Mol Life Sci2006 63505514

    Not in our library10.1007/s00018-005-5472-x

  20. 20.

    Walter JK Castro V Voss M Gast K Rueckert C Piontek J Blasig IE Redox-sensitivity of the dimerization of occludinCell Mol Life Sci2009 6636553662

    Not in our library10.1007/s00018-009-0150-z

  21. 21.

    Walter JK Rueckert C Voss M Mueller SL Piontek J Gast K Blasig IE The oligomerization of the coiled coil-domain of occludin is redox sensitiveAnn N Y Acad Sci2009 11651927

    Not in our library10.1111/j.1749-6632.2009.04058.x

  22. 22.

    Lochhead JJ McCaffrey G Quigley CE Finch J DeMarco KM Nametz N Davis TP Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenationJ Cereb Blood Flow Metab2010 3016251636

    Not in our library10.1038/jcbfm.2010.29

  23. 23.

    Lochhead JJ McCaffrey G Sanchez-Covarrubias L Finch JD Demarco KM Quigley CE Davis TP Ronaldson PT Tempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood–brain barrier during inflammatory painAm J Physiol Heart Circ Physiol2012 302H582593

    Not in our library10.1152/ajpheart.00889.2011

  24. 24.

    McCaffrey G Seelbach MJ Staatz WD Nametz N Quigley C Campos CR Brooks TA Davis TP Occludin oligomeric assembly at tight junctions of the blood–brain barrier is disrupted by peripheral inflammatory hyperalgesiaJ Neurochem2008 10623952409

    Not in our library10.1111/j.1471-4159.2008.05582.x

  25. 25.

    Blasig IE Bellmann C Cording J Del Vecchio G Zwanziger D Huber O Haseloff RF Occludin protein family: oxidative stress and reducing conditionsAntioxid Redox Signal2011 1511951219

    Not in our library10.1089/ars.2010.3542

  26. 26.

    Medina R Rahner C Mitic LL Anderson JM Van Itallie CM Occludin localization at the tight junction requires the second extracellular loopJ Membr Biol2000 178235247

    Not in our library10.1007/s002320010031

  27. 27.

    Wong V Gumbiner BM A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrierJ Cell Biol1997 136399409

    Not in our library10.1083/jcb.136.2.399

  28. 28.

    Tavelin S Hashimoto K Malkinson J Lazorova L Toth I Artursson P A new principle for tight junction modulation based on occludin peptidesMol Pharmacol2003 6415301540

    Not in our library10.1124/mol.64.6.1530

  29. 29.

    Everett RS Vanhook MK Barozzi N Toth I Johnson LG Specific modulation of airway epithelial tight junctions by apical application of an occludin peptideMol Pharmacol2006 69492500

    Not in our library10.1124/mol.105.017251

  30. 30.

    Furuse M Fujimoto K Sato N Hirase T Tsukita S Overexpression of occludin, a tight junction-associated integral membrane protein, induces the formation of intracellular multilamellar bodies bearing tight junction-like structuresJ Cell Sci1996 109Pt 2429435

    Not in our library10.1242/jcs.109.2.429

  31. 31.

    McCarthy KM Skare IB Stankewich MC Furuse M Tsukita S Rogers RA Lynch RD Schneeberger EE Occludin is a functional component of the tight junctionJ Cell Sci1996 109Pt 922872298

    Not in our library10.1242/jcs.109.9.2287

  32. 32.
    Neisseria meningitidis Induces Brain Microvascular Endothelial Cell Detachment from the Matrix and Cleavage of Occludin: A Role for MMP-8 · 2010
    No notice
  33. 33.

    Xu R Feng X Xie X Zhang J Wu D Xu L HIV-1 Tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9Brain Res2012 14361319

    Not in our library10.1016/j.brainres.2011.11.052

  34. 34.

    Moroi S Saitou M Fujimoto K Sakakibara A Furuse M Yoshida O Tsukita S Occludin is concentrated at tight junctions of mouse/rat but not human/guinea pig Sertoli cells in testesAm J Physiol1998 274C17081717

    Not in our library10.1152/ajpcell.1998.274.6.c1708

  35. 35.

    Saitou M Fujimoto K Doi Y Itoh M Fujimoto T Furuse M Takano H Noda T Tsukita S Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctionsJ Cell Biol1998 141397408

    Not in our library10.1083/jcb.141.2.397

  36. 36.
    Complex Phenotype of Mice Lacking Occludin, a Component of Tight Junction Strands · 2000
    Not checked
  37. 37.

    Schulzke JD Gitter AH Mankertz J Spiegel S Seidler U Amasheh S Saitou M Tsukita S Fromm M Epithelial transport and barrier function in occludin-deficient miceBiochim Biophys Acta2005 16693442

    Not in our library10.1016/j.bbamem.2005.01.008

  38. 38.

    Furuse M Sasaki H Tsukita S Manner of interaction of heterogeneous claudin species within and between tight junction strandsJ Cell Biol1999 147891903

    Not in our library10.1083/jcb.147.4.891

  39. 39.

    Mineta K Yamamoto Y Yamazaki Y Tanaka H Tada Y Saito K Tamura A Igarashi M Endo T Takeuchi K Tsukita S Predicted expansion of the claudin multigene familyFEBS Lett2011 585606612

    Not in our library10.1016/j.febslet.2011.01.028

  40. 40.
    Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands · 1999
    Not checked
  41. 41.

    Wolburg H Wolburg-Buchholz K Kraus J Rascher-Eggstein G Liebner S Hamm S Duffner F Grote EH Risau W Engelhardt B Localization of claudin-3 in tight junctions of the blood–brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiformeActa Neuropathol2003 105586592

    Not in our library10.1007/s00401-003-0688-z

  42. 42.

    Morita K Sasaki H Furuse M Tsukita S Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cellsJ Cell Biol1999 147185194

    Not in our library10.1083/jcb.147.1.185

  43. 43.

    Nitta T Hata M Gotoh S Seo Y Sasaki H Hashimoto N Furuse M Tsukita S Size-selective loosening of the blood–brain barrier in claudin-5-deficient miceJ Cell Biol2003 161653660

    Not in our library10.1083/jcb.200302070

  44. 44.

    Ohtsuki S Sato S Yamaguchi H Kamoi M Asashima T Terasaki T Exogenous expression of claudin-5 induces barrier properties in cultured rat brain capillary endothelial cellsJ Cell Physiol2007 2108186

    Not in our library10.1002/jcp.20823

  45. 45.

    Piehl C Piontek J Cording J Wolburg H Blasig IE Participation of the second extracellular loop of claudin-5 in paracellular tightening against ions, small and large moleculesCell Mol Life Sci2010 6721312140

    Not in our library10.1007/s00018-010-0332-8

  46. 46.

    Piontek J Winkler L Wolburg H Muller SL Zuleger N Piehl C Wiesner B Krause G Blasig IE Formation of tight junction: determinants of homophilic interaction between classic claudinsFASEB J2008 22146158

    Not in our library10.1096/fj.07-8319com

  47. 47.

    Zhang J Piontek J Wolburg H Piehl C Liss M Otten C Christ A Willnow TE Blasig IE Abdelilah-Seyfried S Establishment of a neuroepithelial barrier by Claudin5a is essential for zebrafish brain ventricular lumen expansionProc Natl Acad Sci USA2010 10714251430

    Not in our library10.1073/pnas.0911996107

  48. 48.

    Coyne CB Gambling TM Boucher RC Carson JL Johnson LG Role of claudin interactions in airway tight junctional permeabilityAm J Physiol Lung Cell Mol Physiol2003 285L11661178

    Not in our library10.1152/ajplung.00182.2003

  49. 49.

    Piontek J Fritzsche S Cording J Richter S Hartwig J Walter M Yu D Turner JR Gehring C Rahn HP Elucidating the principles of the molecular organization of heteropolymeric tight junction strandsCell Mol Life Sci2011 6839033918

    Not in our library10.1007/s00018-011-0680-z

  50. 50.

    Bazzoni G Pathobiology of junctional adhesion moleculesAntioxid Redox Signal2011 1512211234

    Not in our library10.1089/ars.2010.3867

  51. 51.

    Ebnet K Suzuki A Ohno S Vestweber D Junctional adhesion molecules (JAMs): more molecules with dual functions?J Cell Sci2004 1171929

    Not in our library10.1242/jcs.00930

  52. 52.

    Stevenson BR Siliciano JD Mooseker MS Goodenough DA Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epitheliaJ Cell Biol1986 103755766

    Not in our library10.1083/jcb.103.3.755

  53. 53.

    Gumbiner B Lowenkopf T Apatira D Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1Proc Natl Acad Sci USA1991 8834603464

    Not in our library10.1073/pnas.88.8.3460

  54. 54.

    Haskins J Gu L Wittchen ES Hibbard J Stevenson BR ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludinJ Cell Biol1998 141199208

    Not in our library10.1083/jcb.141.1.199

  55. 55.

    Fanning AS Jameson BJ Jesaitis LA Anderson JM The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeletonJ Biol Chem1998 2732974529753

    Not in our library10.1074/jbc.273.45.29745

  56. 56.

    Itoh M Morita K Tsukita S Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha cateninJ Biol Chem1999 27459815986

    Not in our library10.1074/jbc.274.9.5981

  57. 57.

    Itoh M Furuse M Morita K Kubota K Saitou M Tsukita S Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudinsJ Cell Biol1999 14713511363

    Not in our library10.1083/jcb.147.6.1351

  58. 58.

    Bazzoni G Martinez-Estrada OM Orsenigo F Cordenonsi M Citi S Dejana E Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludinJ Biol Chem2000 2752052020526

    Not in our library10.1074/jbc.m905251199

  59. 59.

    Furuse M Itoh M Hirase T Nagafuchi A Yonemura S Tsukita S Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctionsJ Cell Biol1994 12716171626

    Not in our library10.1083/jcb.127.6.1617

  60. 60.

    Umeda K Ikenouchi J Katahira-Tayama S Furuse K Sasaki H Nakayama M Matsui T Tsukita S Furuse M ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formationCell2006 126741754

    Not in our library10.1016/j.cell.2006.06.043

  61. 61.

    Nusrat A Brown GT Tom J Drake A Bui TT Quan C Mrsny RJ Multiple protein interactions involving proposed extracellular loop domains of the tight junction protein occludinMol Biol Cell2005 1617251734

    Not in our library10.1091/mbc.e04-06-0465

  62. 62.

    Fanning AS Ma TY Anderson JM Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1FASEB J2002 1618351837

    Not in our library10.1096/fj.02-0121fje

  63. 63.

    Izumi Y Hirose T Tamai Y Hirai S Nagashima Y Fujimoto T Tabuse Y Kemphues KJ Ohno S An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of caenorhabditis elegans polarity protein PAR-3J Cell Biol1998 14395106

    Not in our library10.1083/jcb.143.1.95

  64. 64.

    Ebnet K Aurrand-Lions M Kuhn A Kiefer F Butz S Zander K Meyer zu Brickwedde MK Suzuki A Imhof BA Vestweber D The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarityJ Cell Sci2003 11638793891

    Not in our library10.1242/jcs.00704

  65. 65.

    Ebnet K Suzuki A Horikoshi Y Hirose T Meyer Zu Brickwedde MK Ohno S Vestweber D The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM)EMBO J2001 2037383748

    Not in our library10.1093/emboj/20.14.3738

  66. 66.

    Itoh M Sasaki H Furuse M Ozaki H Kita T Tsukita S Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctionsJ Cell Biol2001 154491497

    Not in our library10.1083/jcb.200103047

  67. 67.

    Suzuki A Yamanaka T Hirose T Manabe N Mizuno K Shimizu M Akimoto K Izumi Y Ohnishi T Ohno S Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structuresJ Cell Biol2001 15211831196

    Not in our library10.1083/jcb.152.6.1183

  68. 68.

    Joberty G Petersen C Gao L Macara IG The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42Nat Cell Biol2000 2531539

    Not in our library10.1038/35019573

  69. 69.

    Lin D Edwards AS Fawcett JP Mbamalu G Scott JD Pawson T A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarityNat Cell Biol2000 2540547

    Not in our library10.1038/35019582

  70. 70.
    The Mouse Blood-Brain Barrier Transcriptome: A New Resource for Understanding the Development and Function of Brain Endothelial Cells · 2010
    No notice
  71. 71.

    Denker BM Saha C Khawaja S Nigam SK Involvement of a heterotrimeric G protein alpha subunit in tight junction biogenesisJ Biol Chem1996 2712575025753

    Not in our library10.1074/jbc.271.42.25750

  72. 72.

    Saha C Nigam SK Denker BM Involvement of Galphai2 in the maintenance and biogenesis of epithelial cell tight junctionsJ Biol Chem1998 2732162921633

    Not in our library10.1074/jbc.273.34.21629

  73. 73.

    Fabian G Szabo CA Bozo B Greenwood J Adamson P Deli MA Joo F Krizbai IA Szucs M Expression of G-protein subtypes in cultured cerebral endothelial cellsNeurochem Int1998 33179185

    Not in our library10.1016/s0197-0186(98)00008-4

  74. 74.

    Adamson P Wilbourn B Etienne-Manneville S Calder V Beraud E Milligan G Couraud PO Greenwood J Lymphocyte trafficking through the blood–brain barrier is dependent on endothelial cell heterotrimeric G-protein signalingFASEB J2002 1611851194

    Not in our library10.1096/fj.02-0035com

  75. 75.

    Pero RS Borchers MT Spicher K Ochkur SI Sikora L Rao SP Abdala-Valencia H O’Neill KR Shen H McGarry MP Galphai2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasationProc Natl Acad Sci USA2007 10443714376

    Not in our library10.1073/pnas.0700185104

  76. 76.

    Abbott NJ Ronnback L Hansson E Astrocyte-endothelial interactions at the blood–brain barrierNat Rev Neurosci2006 74153

    Not in our library10.1038/nrn1824

  77. 77.

    Janzer RC Raff MC Astrocytes induce blood–brain barrier properties in endothelial cellsNature1987 325253257

    Not in our library10.1038/325253a0

  78. 78.
    The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival · 2011
    No notice
  79. 79.

    Sa-Pereira I Brites D Brito MA Neurovascular unit: a focus on pericytesMol Neurobiol2012 45327347

    Not in our library10.1007/s12035-012-8244-2

  80. 80.
    Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling · 2010
    No notice
  81. 81.

    Arthur FE Shivers RR Bowman PD Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro modelBrain Res1987 433155159

    Not in our library10.1016/0165-3806(87)90075-7

  82. 82.

    Colgan OC Collins NT Ferguson G Murphy RP Birney YA Cahill PA Cummins PM Influence of basolateral condition on the regulation of brain microvascular endothelial tight junction properties and barrier functionBrain Res2008 11938492

    Not in our library10.1016/j.brainres.2007.11.072

  83. 83.

    Lee SW Kim WJ Choi YK Song HS Son MJ Gelman IH Kim YJ Kim KW SSeCKS regulates angiogenesis and tight junction formation in blood–brain barrierNat Med2003 9900906

    Not in our library10.1038/nm889

  84. 84.

    Neuhaus J Risau W Wolburg H Induction of blood–brain barrier characteristics in bovine brain endothelial cells by rat astroglial cells in transfilter cocultureAnn N Y Acad Sci1991 633578580

    Not in our library10.1111/j.1749-6632.1991.tb15667.x

  85. 85.

    Rubin LL Hall DE Porter S Barbu K Cannon C Horner HC Janatpour M Liaw CW Manning K Morales J A cell culture model of the blood–brain barrierJ Cell Biol1991 11517251735

    Not in our library10.1083/jcb.115.6.1725

  86. 86.

    Tao-Cheng JH Nagy Z Brightman MW Tight junctions of brain endothelium in vitro are enhanced by astrogliaJ Neurosci1987 732933299

    Not in our library10.1523/jneurosci.07-10-03293.1987

  87. 87.

    Wolburg H Neuhaus J Kniesel U Krauss B Schmid EM Ocalan M Farrell C Risau W Modulation of tight junction structure in blood–brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytesJ Cell Sci1994 107Pt 513471357

    Not in our library10.1242/jcs.107.5.1347

  88. 88.

    Hori S Ohtsuki S Hosoya K Nakashima E Terasaki T A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitroJ Neurochem2004 89503513

    Not in our library10.1111/j.1471-4159.2004.02343.x

  89. 89.

    Daneman R Zhou L Kebede AA Barres BA Pericytes are required for blood–brain barrier integrity during embryogenesisNature2010 468562566

    Not in our library10.1038/nature09513

  90. 90.

    Armulik A Genove G Mae M Nisancioglu MH Wallgard E Niaudet C He L Norlin J Lindblom P Strittmatter K Pericytes regulate the blood–brain barrierNature2010 468557561

    Not in our library10.1038/nature09522

  91. 91.

    Dohgu S Takata F Yamauchi A Nakagawa S Egawa T Naito M Tsuruo T Sawada Y Niwa M Kataoka Y Brain pericytes contribute to the induction and up-regulation of blood–brain barrier functions through transforming growth factor-beta productionBrain Res2005 1038208215

    Not in our library10.1016/j.brainres.2005.01.027

  92. 92.

    Liebner S Czupalla CJ Wolburg H Current concepts of blood–brain barrier developmentInt J Dev Biol2011 55467476

    Not in our library10.1387/ijdb.103224sl

  93. 93.

    Osada T Gu YH Kanazawa M Tsubota Y Hawkins BT Spatz M Milner R del Zoppo GJ Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by beta(1)-integrinsJ Cereb Blood Flow Metab2011 3119721985

    Not in our library10.1038/jcbfm.2011.99

  94. 94.

    Zovein AC Luque A Turlo KA Hofmann JJ Yee KM Becker MS Fassler R Mellman I Lane TF Iruela-Arispe ML Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanismDev Cell2010 183951

    Not in our library10.1016/j.devcel.2009.12.006

  95. 95.

    Alvarez JI Dodelet-Devillers A Kebir H Ifergan I Fabre PJ Terouz S Sabbagh M Wosik K Bourbonniere L Bernard M The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescenceScience2011 33417271731

    Not in our library10.1126/science.1206936

  96. 96.

    Liebner S Corada M Bangsow T Babbage J Taddei A Czupalla CJ Reis M Felici A Wolburg H Fruttiger M Wnt/beta-catenin signaling controls development of the blood–brain barrierJ Cell Biol2008 183409417

    Not in our library10.1083/jcb.200806024

  97. 97.

    Taddei A Giampietro C Conti A Orsenigo F Breviario F Pirazzoli V Potente M Daly C Dimmeler S Dejana E Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5Nat Cell Biol2008 10923934

    Not in our library10.1038/ncb1752

  98. 98.

    Lampugnani MG Orsenigo F Rudini N Maddaluno L Boulday G Chapon F Dejana E CCM1 regulates vascular-lumen organization by inducing endothelial polarityJ Cell Sci2010 12310731080

    Not in our library10.1242/jcs.059329

  99. 99.

    Chien AJ Conrad WH Moon RT A Wnt survival guide: from flies to human diseaseJ Invest Dermatol2009 12916141627

    Not in our library10.1038/jid.2008.445

  100. 100.

    Stenman JM Rajagopal J Carroll TJ Ishibashi M McMahon J McMahon AP Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculatureScience2008 32212471250

    Not in our library10.1126/science.1164594

  101. 101.

    Ye X Wang Y Cahill H Yu M Badea TC Smallwood PM Peachey NS Nathans J Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularizationCell2009 139285298

    Not in our library10.1016/j.cell.2009.07.047

  102. 102.

    Daneman R Agalliu D Zhou L Kuhnert F Kuo CJ Barres BA Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesisProc Natl Acad Sci USA2009 106641646

    Not in our library10.1073/pnas.0805165106

  103. 103.

    Paolinelli R Corada M Orsenigo F Dejana E The molecular basis of the blood brain barrier differentiation and maintenance. Is it still a mystery?Pharmacol Res2011 63165171

    Not in our library10.1016/j.phrs.2010.11.012

  104. 104.

    Wu C Ivars F Anderson P Hallmann R Vestweber D Nilsson P Robenek H Tryggvason K Song J Korpos E Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brainNat Med2009 15519527

    Not in our library10.1038/nm.1957

  105. 105.

    Barber AJ Lieth E Agrin accumulates in the brain microvascular basal lamina during development of the blood–brain barrierDev Dyn1997 2086274

    Not in our library10.1002/(sici)1097-0177(199701)208:1<62::aid-aja6>3.0.co;2-#

  106. 106.

    Rascher G Fischmann A Kroger S Duffner F Grote EH Wolburg H Extracellular matrix and the blood–brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrinActa Neuropathol2002 1048591

    Not in our library10.1007/s00401-002-0524-x

  107. 107.

    Gavard J Breaking the VE-cadherin bondsFEBS Lett2009 58316

    Not in our library10.1016/j.febslet.2008.11.032

  108. 108.

    Dejana E Giampietro C Vascular endothelial-cadherin and vascular stabilityCurr Opin Hematol2012 19218223

    Not in our library10.1097/moh.0b013e3283523e1c

  109. 109.

    Harris ES Nelson WJ VE-cadherin: at the front, center, and sides of endothelial cell organization and functionCurr Opin Cell Biol2010 22651658

    Not in our library10.1016/j.ceb.2010.07.006

  110. 110.

    Stanness KA Westrum LE Fornaciari E Mascagni P Nelson JA Stenglein SG Myers T Janigro D Morphological and functional characterization of an in vitro blood–brain barrier modelBrain Res1997 771329342

    Not in our library10.1016/s0006-8993(97)00829-9

  111. 111.

    Mairey E Genovesio A Donnadieu E Bernard C Jaubert F Pinard E Seylaz J Olivo-Marin JC Nassif X Dumenil G Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrierJ Exp Med2006 20319391950

    Not in our library10.1084/jem.20060482

  112. 112.

    Santaguida S Janigro D Hossain M Oby E Rapp E Cucullo L Side by side comparison between dynamic versus static models of blood–brain barrier in vitro: a permeability studyBrain Res2006 1109113

    Not in our library10.1016/j.brainres.2006.06.027

  113. 113.

    Colgan OC Ferguson G Collins NT Murphy RP Meade G Cahill PA Cummins PM Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stressAm J Physiol Heart Circ Physiol2007 292H31903197

    Not in our library10.1152/ajpheart.01177.2006

  114. 114.

    Krizanac-Bengez L Mayberg MR Cunningham E Hossain M Ponnampalam S Parkinson FE Janigro D Loss of shear stress induces leukocyte-mediated cytokine release and blood–brain barrier failure in dynamic in vitro blood–brain barrier modelJ Cell Physiol2006 2066877

    Not in our library10.1002/jcp.20429

  115. 115.

    Siddharthan V Kim YV Liu S Kim KS Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cellsBrain Res2007 11473950

    Not in our library10.1016/j.brainres.2007.02.029

  116. 116.
    The role of shear stress in Blood-Brain Barrier endothelial physiology · 2011
    No notice
  117. 117.

    Walsh TG Murphy RP Fitzpatrick P Rochfort KD Guinan AF Murphy A Cummins PM Stabilization of brain microvascular endothelial barrier function by shear stress involves VE-cadherin signaling leading to modulation of pTyr-occludin levelsJ Cell Physiol2011 22630533063

    Not in our library10.1002/jcp.22655

  118. 118.

    Cummins PM Occludin: one protein, many formsMol Cell Biol2012 32242250

    Not in our library10.1128/mcb.06029-11

  119. 119.
    Modulation of Tight Junction Structure and Function by Kinases and Phosphatases Targeting Occludin · 2012
    No notice
  120. 120.

    Soma T Chiba H Kato-Mori Y Wada T Yamashita T Kojima T Sawada N Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMPExp Cell Res2004 300202212

    Not in our library10.1016/j.yexcr.2004.07.012

  121. 121.

    Willis CL Meske DS Davis TP Protein kinase C activation modulates reversible increase in cortical blood–brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenationJ Cereb Blood Flow Metab2010 3018471859

    Not in our library10.1038/jcbfm.2010.119

  122. 122.

    Kanmogne GD Schall K Leibhart J Knipe B Gendelman HE Persidsky Y HIV-1 gp120 compromises blood–brain barrier integrity and enhances monocyte migration across blood–brain barrier: implication for viral neuropathogenesisJ Cereb Blood Flow Metab2007 27123134

    Not in our library10.1038/sj.jcbfm.9600330

  123. 123.

    Yamamoto M Ramirez SH Sato S Kiyota T Cerny RL Kaibuchi K Persidsky Y Ikezu T Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cellsAm J Pathol2008 172521533

    Not in our library10.2353/ajpath.2008.070076

  124. 124.

    Stamatovic SM Dimitrijevic OB Keep RF Andjelkovic AV Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeabilityJ Biol Chem2006 28183798388

    Not in our library10.1074/jbc.m513122200

  125. 125.

    Haorah J Knipe B Leibhart J Ghorpade A Persidsky Y Alcohol-induced oxidative stress in brain endothelial cells causes blood–brain barrier dysfunctionJ Leukoc Biol2005 7812231232

    Not in our library10.1189/jlb.0605340

  126. 126.

    Haorah J Heilman D Knipe B Chrastil J Leibhart J Ghorpade A Miller DW Persidsky Y Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood–brain barrier compromiseAlcohol Clin Exp Res2005 299991009

    Not in our library10.1097/01.alc.0000166944.79914.0a

  127. 127.

    Kuhlmann CR Tamaki R Gamerdinger M Lessmann V Behl C Kempski OS Luhmann HJ Inhibition of the myosin light chain kinase prevents hypoxia-induced blood–brain barrier disruptionJ Neurochem2007 102501507

    Not in our library10.1111/j.1471-4159.2007.04506.x

  128. 128.

    Takenaga Y Takagi N Murotomi K Tanonaka K Takeo S Inhibition of Src activity decreases tyrosine phosphorylation of occludin in brain capillaries and attenuates increase in permeability of the blood–brain barrier after transient focal cerebral ischemiaJ Cereb Blood Flow Metab2009 2910991108

    Not in our library10.1038/jcbfm.2009.30

  129. 129.

    Andras IE Deli MA Veszelka S Hayashi K Hennig B Toborek M The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cellsJ Cereb Blood Flow Metab2007 2714311443

    Not in our library10.1038/sj.jcbfm.9600445

  130. 130.

    Shen W Li S Chung SH Zhu L Stayt J Su T Couraud PO Romero IA Weksler B Gillies MC Tyrosine phosphorylation of VE-cadherin and claudin-5 is associated with TGF-beta1-induced permeability of centrally derived vascular endotheliumEur J Cell Biol2011 90323332

    Not in our library10.1016/j.ejcb.2010.10.013

  131. 131.

    Staddon JM Herrenknecht K Smales C Rubin LL Evidence that tyrosine phosphorylation may increase tight junction permeabilityJ Cell Sci1995 108Pt 2609619

    Not in our library10.1242/jcs.108.2.609

  132. 132.

    Stamatovic SM Keep RF Wang MM Jankovic I Andjelkovic AV Caveolae-mediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cellsJ Biol Chem2009 2841905319066

    Not in our library10.1074/jbc.m109.000521

  133. 133.

    Tai LM Holloway KA Male DK Loughlin AJ Romero IA Amyloid-beta-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activationJ Cell Mol Med2010 1411011112

    Not in our library10.1111/j.1582-4934.2009.00717.x

  134. 134.

    Andras IE Pu H Tian J Deli MA Nath A Hennig B Toborek M Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cellsJ Cereb Blood Flow Metab2005 2511591170

    Not in our library10.1038/sj.jcbfm.9600115

  135. 135.

    Fischer S Wiesnet M Marti HH Renz D Schaper W Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cellsJ Cell Physiol2004 198359369

    Not in our library10.1002/jcp.10417

  136. 136.

    Mark KS Davis TP Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenationAm J Physiol Heart Circ Physiol2002 282H14851494

    Not in our library10.1152/ajpheart.00645.2001

  137. 137.

    Koto T Takubo K Ishida S Shinoda H Inoue M Tsubota K Okada Y Ikeda E Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cellsAm J Pathol2007 17013891397

    Not in our library10.2353/ajpath.2007.060693

  138. 138.

    Argaw AT Gurfein BT Zhang Y Zameer A John GR VEGF-mediated disruption of endothelial CLN-5 promotes blood–brain barrier breakdownProc Natl Acad Sci USA2009 10619771982

    Not in our library10.1073/pnas.0808698106

  139. 139.

    Jiao H Wang Z Liu Y Wang P Xue Y Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insultJ Mol Neurosci2011 44130139

    Not in our library10.1007/s12031-011-9496-4

  140. 140.

    Afonso PV Ozden S Prevost MC Schmitt C Seilhean D Weksler B Couraud PO Gessain A Romero IA Ceccaldi PE Human blood–brain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganizationJ Immunol2007 17925762583

    Not in our library10.4049/jimmunol.179.4.2576

  141. 141.

    Schreibelt G Kooij G Reijerkerk A van Doorn R Gringhuis SI van der Pol S Weksler BB Romero IA Couraud PO Piontek J Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signalingFASEB J2007 2136663676

    Not in our library10.1096/fj.07-8329com

  142. 142.

    Clarke H Soler AP Mullin JM Protein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheetsJ Cell Sci2000 113Pt 1831873196

    Not in our library10.1242/jcs.113.18.3187

  143. 143.

    Sakakibara A Furuse M Saitou M Ando-Akatsuka Y Tsukita S Possible involvement of phosphorylation of occludin in tight junction formationJ Cell Biol1997 13713931401

    Not in our library10.1083/jcb.137.6.1393

  144. 144.

    Morgan L Shah B Rivers LE Barden L Groom AJ Chung R Higazi D Desmond H Smith T Staddon JM Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosisNeuroscience2007 147664673

    Not in our library10.1016/j.neuroscience.2007.04.051

  145. 145.

    Ishizaki T Chiba H Kojima T Fujibe M Soma T Miyajima H Nagasawa K Wada I Sawada N Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood–brain-barrier endothelial cells via protein kinase A-dependent and -independent pathwaysExp Cell Res2003 290275288

    Not in our library10.1016/s0014-4827(03)00354-9

  146. 146.

    Bruckener KE El Baya A Galla HJ Schmidt MA Permeabilization in a cerebral endothelial barrier model by pertussis toxin involves the PKC effector pathway and is abolished by elevated levels of cAMPJ Cell Sci2003 11618371846

    Not in our library10.1242/jcs.00378

  147. 147.

    Desai TR Leeper NJ Hynes KL Gewertz BL Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathwayJ Surg Res2002 104118123

    Not in our library10.1006/jsre.2002.6415

  148. 148.

    Andreeva AY Krause E Muller EC Blasig IE Utepbergenov DI Protein kinase C regulates the phosphorylation and cellular localization of occludinJ Biol Chem2001 2763848038486

    Not in our library10.1074/jbc.m104923200

  149. 149.

    Stuart RO Nigam SK Regulated assembly of tight junctions by protein kinase CProc Natl Acad Sci USA1995 9260726076

    Not in our library10.1073/pnas.92.13.6072

  150. 150.

    Hofmann J The potential for isoenzyme-selective modulation of protein kinase CFASEB J1997 11649669

    Not in our library10.1096/fasebj.11.8.9240967

  151. 151.

    Fleegal MA Hom S Borg LK Davis TP Activation of PKC modulates blood–brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenationAm J Physiol Heart Circ Physiol2005 289H20122019

    Not in our library10.1152/ajpheart.00495.2005

  152. 152.

    Andreeva AY Piontek J Blasig IE Utepbergenov DI Assembly of tight junction is regulated by the antagonism of conventional and novel protein kinase C isoformsInt J Biochem Cell Biol2006 38222233

    Not in our library10.1016/j.biocel.2005.09.001

  153. 153.

    Harrington EO Brunelle JL Shannon CJ Kim ES Mennella K Rounds S Role of protein kinase C isoforms in rat epididymal microvascular endothelial barrier functionAm J Respir Cell Mol Biol2003 28626636

    Not in our library10.1165/rcmb.2002-0085oc

  154. 154.

    Sonobe Y Takeuchi H Kataoka K Li H Jin S Mimuro M Hashizume Y Sano Y Kanda T Mizuno T Suzumura A Interleukin-25 expressed by brain capillary endothelial cells maintains blood–brain barrier function in a protein kinase Cepsilon-dependent mannerJ Biol Chem2009 2843183431842

    Not in our library10.1074/jbc.m109.025940

  155. 155.

    Goldstein B Macara IG The PAR proteins: fundamental players in animal cell polarizationDev Cell2007 13609622

    Not in our library10.1016/j.devcel.2007.10.007

  156. 156.

    Coureuil M Mikaty G Miller F Lecuyer H Bernard C Bourdoulous S Dumenil G Mege RM Weksler BB Romero IA Meningococcal type IV pili recruit the polarity complex to cross the brain endotheliumScience2009 3258387

    Not in our library10.1126/science.1173196

  157. 157.

    Iden S Rehder D August B Suzuki A Wolburg-Buchholz K Wolburg H Ohno S Behrens J Vestweber D Ebnet K A distinct PAR complex associates physically with VE-cadherin in vertebrate endothelial cellsEMBO Rep2006 712391246

    Not in our library10.1038/sj.embor.7400819

  158. 158.

    Birukova AA Smurova K Birukov KG Kaibuchi K Garcia JG Verin AD Role of Rho GTPases in thrombin-induced lung vascular endothelial cells barrier dysfunctionMicrovasc Res2004 676477

    Not in our library10.1016/j.mvr.2003.09.007

  159. 159.

    Boivin D Bilodeau D Beliveau R Regulation of cytoskeletal functions by Rho small GTP-binding proteins in normal and cancer cellsCan J Physiol Pharmacol1996 74801810

    Not in our library10.1139/y96-083

  160. 160.

    Stamatovic SM Keep RF Kunkel SL Andjelkovic AV Potential role of MCP-1 in endothelial cell tight junction ‘opening’: signaling via Rho and Rho kinaseJ Cell Sci2003 11646154628

    Not in our library10.1242/jcs.00755

  161. 161.

    Persidsky Y Heilman D Haorah J Zelivyanskaya M Persidsky R Weber GA Shimokawa H Kaibuchi K Ikezu T Rho-mediated regulation of tight junctions during monocyte migration across the blood–brain barrier in HIV-1 encephalitis (HIVE)Blood2006 10747704780

    Not in our library10.1182/blood-2005-11-4721

  162. 162.

    Adamson P Etienne S Couraud PO Calder V Greenwood J Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathwayJ Immunol1999 16229642973

    Not in our library

  163. 163.

    Etienne S Adamson P Greenwood J Strosberg AD Cazaubon S Couraud PO ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cellsJ Immunol1998 16157555761

    Not in our library

  164. 164.

    Engelhardt B Wolburg H Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house?Eur J Immunol2004 3429552963

    Not in our library10.1002/eji.200425327

  165. 165.

    Goeckeler ZM Wysolmerski RB Myosin light chain kinase-regulated endothelial cell contraction: the relationship between isometric tension, actin polymerization, and myosin phosphorylationJ Cell Biol1995 130613627

    Not in our library10.1083/jcb.130.3.613

  166. 166.

    Hixenbaugh EA Goeckeler ZM Papaiya NN Wysolmerski RB Silverstein SC Huang AJ Stimulated neutrophils induce myosin light chain phosphorylation and isometric tension in endothelial cellsAm J Physiol1997 273H981988

    Not in our library10.1152/ajpheart.1997.273.2.h981

  167. 167.

    Moy AB Shasby SS Scott BD Shasby DM The effect of histamine and cyclic adenosine monophosphate on myosin light chain phosphorylation in human umbilical vein endothelial cellsJ Clin Invest1993 9211981206

    Not in our library10.1172/jci116690

  168. 168.

    Antonetti DA Barber AJ Hollinger LA Wolpert EB Gardner TW Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumorsJ Biol Chem1999 2742346323467

    Not in our library10.1074/jbc.274.33.23463

  169. 169.

    Nico B Mangieri D Crivellato E Longo V De Giorgis M Capobianco C Corsi P Benagiano V Roncali L Ribatti D HIF activation and VEGF overexpression are coupled with ZO-1 up-phosphorylation in the brain of dystrophic mdx mouseBrain Pathol2007 17399406

    Not in our library10.1111/j.1750-3639.2007.00090.x

  170. 170.

    Kago T Takagi N Date I Takenaga Y Takagi K Takeo S Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillariesBiochem Biophys Res Commun2006 33911971203

    Not in our library10.1016/j.bbrc.2005.11.133

  171. 171.

    Wang W Dentler WL Borchardt RT VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assemblyAm J Physiol Heart Circ Physiol2001 280H434440

    Not in our library10.1152/ajpheart.2001.280.1.h434

  172. 172.

    Frank PG Woodman SE Park DS Lisanti MP Caveolin, caveolae, and endothelial cell functionArterioscler Thromb Vasc Biol2003 2311611168

    Not in our library10.1161/01.atv.0000070546.16946.3a

  173. 173.

    Sprenger RR Fontijn RD van Marle J Pannekoek H Horrevoets AJ Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomesBiochem J2006 400401410

    Not in our library10.1042/bj20060355

  174. 174.

    Nusrat A Parkos CA Verkade P Foley CS Liang TW Innis-Whitehouse W Eastburn KK Madara JL Tight junctions are membrane microdomainsJ Cell Sci2000 113Pt 1017711781

    Not in our library10.1242/jcs.113.10.1771

  175. 175.

    Shen L Turner JR Actin depolymerization disrupts tight junctions via caveolae-mediated endocytosisMol Biol Cell2005 1639193936

    Not in our library10.1091/mbc.e04-12-1089

  176. 176.

    Andras IE Pu H Deli MA Nath A Hennig B Toborek M HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cellsJ Neurosci Res2003 74255265

    Not in our library10.1002/jnr.10762

  177. 177.

    Urban NT Willig KI Hell SW Nagerl UV STED nanoscopy of actin dynamics in synapses deep inside living brain slicesBiophys J2011 10112771284

    Not in our library10.1016/j.bpj.2011.07.027

  178. 178.

    Keene SD Greco TM Parastatidis I Lee SH Hughes EG Balice-Gordon RJ Speicher DW Ischiropoulos H Mass spectrometric and computational analysis of cytokine-induced alterations in the astrocyte secretomeProteomics2009 9768782

    Not in our library10.1002/pmic.200800385

  179. 179.

    Picotti P Aebersold R Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directionsNat Methods2012 9555566

    Not in our library10.1038/nmeth.2015

  180. 180.

    Uchida Y Ohtsuki S Katsukura Y Ikeda C Suzuki T Kamiie J Terasaki T Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptorsJ Neurochem2011 117333345

    Not in our library10.1111/j.1471-4159.2011.07208.x

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