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. Author manuscript; available in PMC: 2011 Oct 1.
Published in final edited form as: Curr Opin Cell Biol. 2010 Aug 11;22(5):651–658. doi: 10.1016/j.ceb.2010.07.006

VE-Cadherin: At the Front, Center, and Sides of Endothelial Cell Organization and Function

Elizabeth S Harris 1,3, W James Nelson 1,2
PMCID: PMC2948582  NIHMSID: NIHMS229676  PMID: 20708398

Summary

Endothelial cells form cell-cell adhesive structures, called adherens and tight junctions, which maintain tissue integrity, but must be dynamic for leukocyte transmigration during the inflammatory response and cellular remodeling during angiogenesis. This review will focus on Vascular Endothelial (VE)-cadherin, an endothelial-specific cell-cell adhesion protein of the adherens junction complex. VE-cadherin plays a key role in endothelial barrier function and angiogenesis, and consequently VE-cadherin availability and function are tightly regulated. VE-cadherin also participates directly and indirectly in intracellular signaling pathways that control cell dynamics and cell cycle progression. Here we highlight recent work that has advanced our understanding of multiple regulatory and signaling mechanisms that converge on VE-cadherin and have consequences for endothelial barrier function and angiogenic remodeling.

Introduction

Endothelial cells form the vasculature and are the major barrier between the blood and the rest of the body. These specialized cells regulate the exchange of solutes and fluids between the blood and tissue and control entry of leukocytes into the surrounding tissue. The endothelium is also the site for angiogenesis, which involves extension and remodeling of blood vessels. Essential for all these functions is the ability of endothelial cells to properly regulate cell-cell adhesions between themselves and neighboring cells. Endothelial dysfunction is often a result of altered permeability of the endothelial cell monolayer and is a hallmark of many pathological and disease states, including atherosclerosis, diabetes, hypertension, inflammation, and tumor metastasis [1,2].

Endothelial cells present a special challenge for the regulation of cell-cell adhesion. On the one hand, the integrity of cell-cell adhesion within the monolayer must be maintained for proper barrier function. On the other hand, cell-cell adhesion must be sufficiently plastic to allow passage of leukocytes as well as growth and development of blood vessels. This review will focus on VE-cadherin, the endothelial-specific transmembrane component of the adherens junction complex [3], which has emerged as a master regulator of endothelial cell-cell adhesive properties.

Endothelial cell junctions

Endothelial cells utilize two types of adhesion complexes to mediate cell-cell interactions, adherens and tight junctions (Figure 1) [4]. Adherens junctions participate in multiple functions, including establishment and maintenance of cell-cell adhesion, actin cytoskeleton remodeling, intracellular signaling, and transcriptional regulation. Tight junctions regulate monolayer permeability, and play a greater role in endothelial cells that maintain stringent barriers, such as those that constitute the blood-brain barrier. Adherens junction assembly and organization precedes formation of tight junctions. In endothelial cells, adherens and tight junctions are intermingled, whereas in epithelial cells the tight junction is localized apical to the adherens junction

Figure 1.

Figure 1

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Human umbilical vein endothelial cells stained for VE-cadherin (adherens junctions, green), ZO-1 (tight junctions, red), and DAPI (nucleus, blue). Scale bar, 20 microns.

The protein compositions of adherens and tight junctions in endothelial cells are similar to those in epithelial cells [5], with a few exceptions. The transmembrane component of endothelial adherens junction is VE-cadherin (Cadherin-5, CD144), a type-II endothelial-restricted classical cadherin [3], which binds through its cytoplasmic tail to members of the armadillo repeat family of proteins, including p120-catenin, β-catenin, and plakoglobin. p120-Catenin and β-catenin can also shuttle to the nucleus to regulate gene expression. α-Catenin associates indirectly with VE-cadherin by binding to β-catenin and plakoglobin. In addition to these core components of the adherens junction, several other proteins bind VE-cadherin and regulate its activity (discussed below). Endothelial cells also express high levels of Neuronal (N)-cadherin, but it is not clustered at cell-cell contacts between endothelial cells [6,7].

Mouse models in which the VE-cadherin gene was inactivated demonstrate the importance of VE-cadherin for endothelial cell biology. VE-cadherin-deficient mice die in mid-gestation as a result of major defects in vascular remodeling. The primitive vascular plexus initially forms, but beyond E9.25 these vessels regress and disintegrate [8,9]. Similarly, in zebrafish embryos, initial vascular network formation occurs following morpholino-mediated depletion of VE-cadherin, but vessels do not form connections necessary for lumen formation and collapse [10]. VE-cadherin function blocking antibodies disrupt cell-cell adhesion, increase permeability, and enhance transmigration of leukocytes [11,12]. Together, these studies show that VE-cadherin participates in multiple aspects of endothelial cell biology, and is indispensable for maturation, extension, and remodeling of vessels that are characteristic of angiogenesis. Further evidence that the overall integrity of the adherens junction is important for endothelial cell function is supported by conditional inactivation of β-catenin [13] and p120-catenin [14] in mouse endothelial cells. In both cases, vascular defects lead to embryonic death at E11.5–13.5. Other in vivo models of cell-cell adhesion components have been made and are discussed in a recent review [15].

Tight junctions are composed of transmembrane proteins that include claudins, occludins, and junctional adhesion molecules (JAMs). These membrane proteins associate with cytoplasmic proteins including, zonula occludens (ZO), AF-6/afadin, and PAR-3. Of the transmembrane components, claudin-5 is specifically expressed in endothelial cells [16]. Claudin-5 knockout mice die within 10 hours of birth due to a size-selective disruption in blood-brain barrier permeability, but surprisingly overall morphology of the vasculature and ultrastructure of tight junctions is normal [17]. Disruption of claudin-5 also causes increased monolayer permeability in tissue culture cells, but does not alter VE-cadherin localization. On the other hand, VE-cadherin regulates expression of claudin-5 [18••]. VE-cadherin clustering at cell-cell contacts attenuates activity of the forkhead transcriptional repressor FoxO1, resulting in upregulation of claudin-5 mRNA. FoxO1 regulates expression of genes involved in vascular development and remodeling, and FoxO1 null embryos die due to defects in these processes [19,20]. Downregulation of FoxO1 in response to VE-cadherin clustering occurs through two mechanisms: 1) activation of phosphatidylinositol-3 kinase (PI3K)-Akt signaling cascade, which induces phosphorylation and inactivation FoxO1, and 2) reduction in levels of nuclear β-catenin, a binding partner and enhancer of FoxO1 activity [18••]. Thus, in addition to adhesive properties, the role of VE-cadherin as a transducer of intracellular signals is critical to maintain proper endothelial cell function.

VE-cadherin regulation

VE-cadherin is essential for controlling endothelial monolayer permeability and angiogenesis. There are many mechanisms that regulate VE-cadherin including, modulating VE-cadherin activity through phosphorylation and controlling the amount of VE-cadherin available for engagement at adherens junctions at both the protein and mRNA level (Figure 2A).

Figure 2.

Figure 2

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Schematic of VE-cadherin regulation and signaling. Numbers correspond to labeling on figure. For simplicity, only p120-catenin and β-catenin are shown bound to VE-cadherin; plakoglobin and α-catenin have been omitted. (A) Mechanisms that modulate VE-cadherin activity include: (1) changes in VE-cadherin gene expression through activity of Erg/Ets-1, TAL-1/SCL, and Twist/Slug/Snail transcription factors; (2) trafficking via Golgi-associated protein cPLA2α; (3) transport along actin filaments via myosin-X; (4) stabilization at the plasma membrane by p120-catenin, which is enhanced by FGF; (5) phosphorylation induced by permeability factors (e.g. VEGF, TNF-α, PAF, thrombin, histamine, IL-8) which signal through various kinases to promote disassembly of the adherens junction complex and/or VE-cadherin internalization; (6) phosphorylation induced by leukocytes which promotes disassembly of the adherens junction complex; and (7) inhibition of phosphorylation by PTPs or Ang1. (B) Mechanisms by which VE-cadherin can transduce intracellular signals include: (8) indirect binding to VEGF-R2, which prevents its phosphorylation, internalization, and signaling to MAPK; (9) binding to and assembly of TGF-β receptor complex, which enhances Smad-dependent transcription; signaling through small GTPases including (10) Rho/ROCK to promote actomyosin contraction, (11) Rac1/Tiam1, and (12) Rap1/Epac; and indirect regulation of gene transcription by (13) limiting the amount of p120-catenin and β-catenin that can translocate to the nucleus and (14) inhibiting FoxO1, which leads to an increase in claudin-5 mRNA.

Phosphorylation of VE-cadherin

It is generally accepted that phosphorylation of VE-cadherin leads to destabilization of the adherens junction complex and increased monolayer permeability, although which residues are phosphorylated and important for modifying VE-cadherin activity is less clear.

Several soluble factors such as vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), platelet-activating factor (PAF), thrombin, and histamine induce tyrosine phosphorylation of VE-cadherin, which correlates with an increase in vascular permeability [21]. These factors also lead to phosphorylation of β-catenin, p120-catenin, and plakoglobin, suggesting that phosphorylation of other components of the adherens junction complex promotes disruption of cell-cell contacts. The molecular mechanism(s) down-stream of these soluble factors that result in VE-cadherin phosphorylation, and how this leads to increased permeability is currently an area of intense investigation.

VEGF was originally identified as a potent factor for inducing endothelial permeability [22], and was shown subsequently to induced tyrosine phosphorylation of the adherens junction complex [23]. VEGF stimulation results in Src tyrosine kinase-mediated phosphorylation of VE-cadherin on Y685 [24]. Mice lacking Src or treated with Src inhibitors do not show an increase in vascular permeability in response to VEGF [25,26], suggesting that Src-mediated phosphorylation of VE-cadherin induced by VEGF is a major regulatory pathway that modifies the structural integrity of cell-cell contacts.

VEGF also induces tyrosine phosphorylation of additional residues on VE-cadherin. VEGF stimulation promoted Rac1-dependent production of reactive oxygen species, resulting in phosphorylation of VE-cadherin on Y658 and Y731. This results in the disorganization of cell-cell contacts and increased monolayer permeability [27]. TNF-α stimulation also leads to tyrosine phosphorylation of Y658 and Y731 mediated by a signaling cascade initiated by PI3K p100α, including activation of proline-rich tyrosine kinase 2 (Pyk2) and Rac1/Tiam1 [28]. Y658 or Y731 phosphorylation disrupts VE-cadherin association with p120-catenin or β-catenin, respectively [29].

Leukocyte docking to endothelial monolayers also triggers tyrosine phosphorylation of VE-cadherin, an effect mediated by signals induced upon engagement of inter-cellular adhesion molecule (ICAM)-1 [30•,31•]. Activation of Src and Pyk2 in response to ICAM-1 engagement results in phosphorylation of Y658 and Y731 on VE-cadherin. Inhibition of these kinases, or mutation of these residues to non-phosphorylatable amino acids, impairs transmigration of leukocytes [31•]. However, another study showed ICAM-1 engagement promotes phosphorylation of Y645, Y731 and Y733, but not Y658 [30•]. Despite these discrepancies, it seems clear that leukocytes alter the phosphorylation state of VE-cadherin as a general mechanism to weaken cell-cell contacts and promote their efficient transmigration.

Several protein tyrosine phosphatases (PTPs) associate with and dephosphorylate VE-cadherin. These PTPs include vascular endothelial receptor-type PTP (VE-PTP), whose expression is restricted to endothelial cells [32,33]. VE-PTP activity enhances VE-cadherin-mediated cell-cell adhesion, which results in a decrease in endothelial barrier permeability [32]. VE-PTP mutant [34] or knockout mice [35] die in mid-gestation with defects in angiogenic remodeling, similar to the VE-cadherin-deficient mice. Thus, the balance between PTP and tyrosine kinase activities is important to regulate the level of VE-cadherin phosphorylation and thereby the degree of endothelial permeability. Interestingly, leukocytes trigger the dissociation of VE-PTP from VE-cadherin [36], further supporting the idea that leukocytes induce changes in the phosphorylation state of VE-cadherin to enhance their transmigration.

While much of the focus has been on understanding the effects of tyrosine phosphorylation of VE-cadherin, serine phosphorylation also plays an important role. VEGF and interleukin-8 (IL-8) both promote phosphorylation of VE-cadherin on S665, which results in increased barrier permeability due to internalization of VE-cadherin [37••,38]. Mutation of this serine residue to a non-phosphorylatable amino acid prevents internalization of VE-cadherin in response to either VEGF or IL-8. Interestingly, these two soluble factors both signal through Rac1, which leads to p21-activated kinase (PAK)-mediated phosphorylation of S665. While VEGF stimulation activates Rac1 through Src-dependent phosphorylation of Vav2 [37••], IL-8 activates Rac1 through CXC chemokine receptor 2 (CXCR2) and activation of PI3Kγ [38]. In summary, tyrosine and serine phosphorylation of VE-cadherin directly affects VE-cadherin stability and protein interactions that, in turn, affect endothelial permeability.

VE-cadherin availability at the cell surface

Cells modulate their adhesive state by controlling the amount of cadherin localized at the cell surface. The direct association of p120-catenin with VE-cadherin prevents clathrin-dependent endocytosis of VE-cadherin [39,40]. The interaction of p120-catenin with VE-cadherin is also necessary for maintaining endothelial barrier function [41] and for proper angiogenic remodeling [14]. Fibroblast growth factor (FGF) signaling, which promotes stabilization of the vasculature and decreases monolayer permeability, increases p120-catenin association with VE-cadherin [42], supporting the idea that the interaction of p120-catenin with VE-cadherin enhances monolayer integrity. Furthermore, overexpression of p120-catenin reduces transmigration of leukocytes mainly due to decreased tyrosine phosphorylation of VE-cadherin on Y658 [43•]. Y658 is located in the binding site for p120-catenin and its phosphorylation prevents p120-catenin association with VE-cadherin [27,29]. Phosphorylation of Y658 by Src and Pyk2 promotes efficient transmigration of leukocytes [31•]. By competing with kinases that phosphorylate VE-cadherin, p120-catenin may prevent VE-cadherin internalization from the plasma membrane and enhance monolayer barrier function.

Interaction of VE-cadherin with β-arrestin also regulates the amount of VE-cadherin at the plasma membrane. In contrast to p120-catenin binding, β-arrestin promotes internalization of VE-cadherin into clathrin-coated vesicles in response to VEGF-induced, PAK-mediated phosphorylation of S665 on VE-cadherin [37••]. IL-8 stimulation also leads to PAK-mediated phosphorylation of S665 and internalization of VE-cadherin, but it is not known whether this is mediated by β-arrestin binding [38]. As VEGF (and possibly IL-8) signaling promotes β-arrestin-mediated internalization of VE-cadherin [37••] and FGF signaling promotes p120-catenin-mediated stabilization of VE-cadherin [42], changes in the balance between these pathways may determine permeability properties of the endothelial monolayer. Angiopoietin-1 (Ang1), a proangiogenic factor known to promote stabilization of the vasculature [44], also prevents VEGF-induced phosphorylation of S665 and internalization of VE-cadherin through the inhibition of Src activity [45•]. Thus, Ang1 represents another signaling mechanism to counteract the increase in endothelial permeability by VEGF.

Although the amount of VE-cadherin at the cell surface is regulated at the level of endocytosis, little is know about exocytosis of newly synthesized VE-cadherin. Recently, Golgi-associated phospholipase A2α (cPLA2α) has been implicated in trafficking VE-cadherin to the cell surface [46]. Disruption of cPLA2α results in disorganization of VE-cadherin at the plasma membrane and accumulation of VE-cadherin in intracellular vesicles and the Golgi. Interestingly, the localization of cPLA2α to the Golgi is enhanced as cell monolayers mature, while disruption of VE-cadherin results in dissociation of cPLA2α from the Golgi [46]. This suggests a positive feedback loop mediated by VE-cadherin clustering and/or signaling promotes continued transport of newly synthesized VE-cadherin to the cell surface, thereby maintaining structural integrity of the adherens junction.

The association of VE-cadherin with the motor protein myosin-X also promotes VE-cadherin trafficking to the plasma membrane [47•]. In subconfluent endothelial cells, myosin-X binds and transports VE-cadherin along filopodial actin filaments, leading to accumulation of VE-cadherin at filopodia tips. When these filopodia contact a neighboring cell, VE-cadherin engages in homophilic interactions with the opposing cell forming nascent cell-cell contacts. Blocking the motor activity of myosin-X prevents VE-cadherin transport and formation of early cell-cell contacts [47•]. Thus, endothelium wound repair, which requires establishment of nascent cell-cell contacts between actively migrating cells, may require myosin-X mediated transport of VE-cadherin.

VE-cadherin expression

Several transcription factors regulate VE-cadherin gene expression. ETS transcription factors are expressed early in development and are important for vasculogenesis and angiogenesis [19]. Members of this family, including Erg and Ets-1, bind and enhance VE-cadherin promoter activity [48,49]. Depletion of Erg disrupts VE-cadherin-mediated cell-cell adhesion, increases apoptosis, and decreases vessel formation [50]. The TAL-1/SCL transcription factor, which was originally found to be a key regulator of hematopoiesis but is now known to be equally important for vascular development [51], also binds and activates the VE-cadherin promoter and is required for formation of capillary-like structures in vitro [52].

Exposure of human endothelial cell monolayers to breast cancer cells or conditioned media leads to decreased expression and mis-localization of VE-cadherin [53]. Members of the Twist/Slug/Snail family are responsible for this transcriptional repression due to direct binding to the VE-cadherin promoter [54]. Interestingly, in epithelial cells transcription of Slug is induced by β-catenin signaling, the main effector of the Wnt pathway [55]. Wnt signaling is emerging as an important factor for endothelial cell biology [56], but it has not been reported whether VE-cadherin is a direct transcriptional target of Wnt signaling. However, Wnt-induced upregulation of Slug, which leads to repression of VE-cadherin, may prolong and/or enhance Wnt signaling-mediated affects on endothelial cells by increasing the amount of free β-catenin available for transcription.

VE-cadherin signaling

In addition to adhesive properties, VE-cadherin is an important signaling molecule. Signaling via VE-cadherin influences endothelial cell behavior by modulating activity of growth factor receptors, intracellular messengers, and proteins that regulate gene transcription (Figure 2B).

VE-cadherin engagement with growth factor receptors and intracellular messengers

VE-cadherin associates with two growth factor receptors - VEGF receptor 2 (VEGF-R2) and transforming growth factor-β (TGF-β) receptor. In confluent cells, VE-cadherin binds VEGF-R2 indirectly through β-catenin. This prevents VEGF-induced VEGF-R2 tyrosine phosphorylation and internalization into clathrin-coated vesicles, and reduces mitogen-activated protein kinase (MAPK) activation and proliferative signals [57,58]. In contrast, TGF-β anti-proliferative and anti-migratory signals are enhanced upon VE-cadherin binding to the TGF-β receptor complex. VE-cadherin promotes assembly of the TGF-β receptor complex into an active receptor complex capable of phosphorylating and activating Smad-dependent transcription [59••]. Thus, the effect of VE-cadherin on these two receptors is opposing (inhibition of VEGF-R2, activation of TGF-β receptor complex), but both result in stabilization of the vasculature. It is unknown whether the phosphorylation state of VE-cadherin affects its association with either VEGF-R2 or TGF-β receptor complex, but this could be one potential mechanism to tip the balance between these growth factors, allowing the transition between quiescent and activated cell states.

There is a growing list of intracellular messengers regulated by VE-cadherin, many of which are involved in GTPase signaling. VE-cadherin signals via RhoC to activate Rho kinase (ROCK) and myosin light-chain 2 (MLC2) phosphorylation. This promotes actomyosin contractility, but suppresses VEGF/VEGF-R2-mediated Rac1-dependent angiogenic sprouting. Inhibition of ROCK results in loss of VE-cadherin from the plasma membrane, suggesting a positive feedback loop between VE-cadherin clustering and ROCK activation may maintain integrity of cell-cell contacts [60]. Previous studies also demonstrated VE-cadherin signaling through RhoA-ROCK enhances actomyosin-mediated contractions [61,62]. However, VE-cadherin clustering may also inhibit Rho, while activating Rac1/Tiam1 [63]. Whether VE-cadherin activates Rho or Rac may depend on which upstream signaling messages are received.

VE-cadherin has a reciprocal relationship with the small GTPase Rap1. Signaling through Rap1/Epac decreases monolayer permeability by enhancing VE-cadherin-mediated cell-cell adhesion. VE-cadherin clustering in turn activates Rap1 by creating a scaffold for recruitment of the Rap1 activator PDZ-GEF1 [64]. Another effector of Rap1, cerebral cavernous malformation-1 (CCM-1), also stabilizes VE-cadherin at cell-cell contacts, thereby increasing monolayer integrity and promoting proper formation and maintenance of the vascular lumen [65,66]. Mutations in CCM-1 result in a human disease associated with defective endothelial cell-cell junctions and abnormal vasculature [2]. Thus, the Rap1-VE-cadherin signaling axis appears critical for proper endothelial cell function.

VE-cadherin regulation of transcription

As noted above, VE-cadherin-mediated cell-cell adhesion can indirectly regulate gene transcription by suppressing the transcriptional repressor FoxO1, leading to upregulation of claudin-5 mRNA [18••]. In the adherens junction complex, VE-cadherin associates with p120-catenin and β-catenin, both of which are well known mediators of gene transcription. Endothelial cells treated with the permeability-inducing factor thrombin show translocation of p120-catenin and β-catenin into the nucleus and induction of β-catenin target genes [67], suggesting the assembly of p120-catenin and β-catenin into the adherens junction complex may reduce availability and signaling capabilities of these proteins. However, disrupting VE-cadherin-mediated endothelial cell-cell adhesion by Ca2+ chelation does not induce β-catenin translocation or transcription [68], indicating that simply disrupting cell-cell adhesion is not sufficient to induce gene transcription. Therefore, thrombin (and other factors) may trigger additional signaling events (e.g. phosphorylation of adherens junction proteins) that promote the nuclear signaling functions of these proteins.

In endothelial cells, p120-catenin associates with the transcription factor Kaiso and suppresses its activity [69], similar to its role in non-endothelial cells [70]. The consequences of this interaction on vascular development have not been examined.

Several studies indicate a role for β-catenin-mediated Wnt transcription in endothelial cell biology and vascular development. Using a transgenic reporter mouse, Wnt/β-catenin signaling was shown to be active in endothelial cells [71], and Wnt/β-catenin signaling is critical for blood-brain barrier function [72•,73•]. In addition, several human diseases associated with vascular defects are linked to Wnt/β-catenin pathway, further implicating the importance of this signaling axis for proper endothelial cell function [56]. Interestingly, there is evidence for cross-talk between VEGF and Wnt/β-catenin signaling pathways. β-Catenin signaling enhances expression of VEGF/VEGF-R2 and promotes endothelial cell proliferation and formation of capillary-like structures [74]. Whether VE-cadherin plays a role in regulating transcriptional activity of p120-catenin and β-catenin remains to be determined.

Concluding Remarks

VE-cadherin plays a key role in all branches of endothelial cell biology. Through both its adhesive and signaling properties, VE-cadherin maintains a careful balance between intercellular junction plasticity and integrity, a requirement for endothelial cells to maintain proper barrier function of blood vessels while still being capable of dynamically responding to inflammatory and growth factor signals. Deciphering the molecular mechanism(s) of different regulatory and signaling pathways that act on, or are initiated by VE-cadherin, and understanding how they contribute to endothelial cell biology, is an important area for future research. These studies may lead to the discovery of new therapeutic targets for the many inherited and pathological diseases associated with endothelial dysfunction.

Acknowledgements

The authors apologize for inability to cite original sources in some instances due to restrictions in the number of references allowed. This work was supported by NIH grant GM035527 to WJN, and a post-doctoral fellowship from Jane Coffin Childs Fund for Medical Research to ESH.

Footnotes

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