The Role of VE-Cadherin in Vascular Morphogenesis and Permeability Control

doi:10.1016/B978-0-12-394311-8.00006-6

Progress in Molecular Biology and Translational Science

Volume 116, 2013, Pages 119-144

https://doi.org/10.1016/B978-0-12-394311-8.00006-6 Get rights and content

Abstract

VE-cadherin is an endothelial-specific cadherin that is essential for the formation and regulation of endothelial cell junctions. The adhesive function and expression levels of VE-cadherin at endothelial contacts are central determinants of the control of vascular permeability and leukocyte recruitment into tissue. In addition to controlling junctional integrity, VE-cadherin modulates a multitude of signaling processes that influence the behavior of endothelial cells, such as proliferation, survival, migration, polarity, expression of other junctional components, and tube and lumen formation of blood vessels. This chapter highlights recent progress in understanding how VE-cadherin modulates these various cellular processes. In addition, the current knowledge about how VE-cadhern participates in the regulation of the endothelial barrier in the adult organism is discussed.

Introduction

Endothelial cells are linked to each other by two major types of cell–cell junctions named adherens junctions (AJ) and tight junctions (TJ). These structures are formed by transmembrane adhesive proteins, which promote homophilic cell-to-cell adhesion. In turn, the transmembrane proteins are linked to specific intracellular partners, which mediate their anchorage to the actin cytoskeleton and, as a consequence, stabilize junctions.1, 2

Junctions in the endothelium control different features of vascular homeostasis. For instance, permeability to plasma solutes is controlled, to a good extent, by junctions. In addition, leukocyte extravasation and infiltration into inflamed areas require regulated opening and closing of cell-to-cell contacts.3, 4 Notably, junctional proteins can also transfer intracellular signals, which modulate several endothelial-specific functions, including contact inhibition of cell growth, cell polarity, tubulogenesis, resistance to apoptotic stimuli, and others.⁵

Endothelial junctions are highly specialized along the vascular tree according to the specific needs of the organs. For instance, in the brain, where strict control of permeability between the blood and the nervous system is required, junctions are well developed and rich in TJ.⁶ In contrast, in capillary lymphatics, where dynamic traffic of lymphocytes, dendritic cells, and lymph occurs, junctions have different specialized features. In these vessels, junctional adhesive proteins are not organized in zipper-like structures but, instead, form separate and well-defined clusters (buttons) along the cell membrane with membrane flaps in between (Fig. 6.1). These particular structures allow dynamic entrance of cells and solutes, while the membrane flaps form a sort of valve inhibiting their exit.⁷

AJ and TJ are formed by different molecular components, with few exceptions (for a review, see Ref. 1). At TJ, adhesion is mediated by members of the claudin family and endothelial cells express several members of this family (claudin-1, -3, -5, -12, and others) depending on the type of vessel. Claudin-5 is an endothelial-specific claudin present in the endothelium of the majority of vessels. Claudins are linked inside the cells to intracellular partners, which include the members of the ZO family, cingulin, ZONAB, and others. These proteins mediate the anchorage to actin but they may also transfer intracellular signals (for a review, see Ref. 8).

At AJ, on the other hand, adhesion is mediated by members of the cadherin family. In particular, endothelial cells express VE-cadherin (cadherin-5), N-cadherin (cadherin-2) and, in some vessels, also P- (cadherin-3) and T-cadherin (cadherin-13) (see below). VE- and N-cadherins can directly bind armadillo catenins such as β-catenin, plakoglobin, and p120 (for a review, see Ref. 1). As in the case of TJ, these AJ proteins promote junction stability through their interaction with the actin cytoskeleton. As discussed below in more detail, these proteins may also transfer intracellular signals that regulate different vascular functions.

In general, junctions are dynamic structures. In the adult, they can quickly open or close in response to agents that increase permeability or to the passage of leukocytes. Furthermore, endothelial cell-to-cell junctions need to adapt to changes in blood flow and hydrostatic pressure, which accompany the movements of the body. Junction organization may therefore vary not only in different types of vessels but also upon exposure to different hemodynamic conditions.

During vascular development in the embryo, junctions undergo different steps of maturation that parallel vascular remodeling and stabilization.⁹ In the growing vasculature, the vessels are more permeable and adhesion at endothelial cell-to-cell junctions is relatively weak. The intracellular partners of the junctional adhesive proteins may also vary during junction maturation. In addition, even after contacts have been stably formed, adhesion proteins are still in dynamic equilibrium at junctions and recycle continuously between the plasma membrane and intracellular compartments.10, 11

In this review, we focus on the molecular organization and functional changes of AJ and, in particular, of VE-cadherin and its molecular partners. The role of AJ in vascular morphogenesis and in the control of permeability to inflammatory cells and plasma solutes is discussed in detail. In contrast, we consider only marginally the structure and function of TJ in the endothelium. Excellent reviews on TJ organization and function are available in the literature.8, 12

Section snippets

Structural Properties of VE-Cadherin

The structural features of the trans interactions of cadherins have been intensively studied because they form the basis of homophilic, cadherin-specific cell recognition and adhesion. VE-cadherin belongs to the “classical” cadherins, which comprise two major subfamilies named type-I and type-II cadherins (see also Chapter 4). Both types of classical cadherins have five extracellular cadherin (EC) domains. Their elongated and substantially curved structure is stabilized by Ca^2 + ions that bind

General characteristics of VE-cadherin signaling

A major function of VE-cadherin is to promote homotypic cell–cell adhesion and thereby create and maintain endothelial integrity. This property is particularly important during vascular development when single endothelial cells need to preserve adhesion to one another to form new vessels (for review, see 12, 21).

Besides promoting adhesion between endothelial cells, VE-cadherin and AJ, in general, can transfer intracellular signals. The signaling network transduced by VE-cadherin is quite

VE-Cadherin and N-Cadherin Cross Talk

Even if VE-cadherin is the most prominent cadherin at endothelial AJs, it is not the only cadherin expressed in endothelial cells. N-cadherin can be found at comparable levels in most of the endothelial cells examined so far.61, 80 P-cadherin expression was detected by PCR analysis and T-cadherin was also found in the vasculature in tissue sections.⁸¹

N-cadherin is not endothelial specific as it is also present in other cell types, including neuronal cells, lens cells, skeletal and heart muscle

Tyrosine phosphorylation of the VE-cadherin–catenin complex

The homophilic adhesive function of VE-cadherin was initially established by analyzing CHO cells transfected with VE-cadherin cDNA.⁸² By using blocking antibodies against VE-cadherin, various laboratories demonstrated that the function of VE-cadherin is essential for the maintenance of endothelial cell contact stability. These antibodies abrogated cell contact stability in vitro between cultured endothelial cells as well as in vivo in mice, causing vascular leaks as well as enhancing

Conclusions

VE-cadherin is a strictly endothelial-specific adhesion molecule that influences a broad spectrum of cellular responses of endothelial cell biology. Knowledge of the molecular processes that are influenced by VE-cadherin and that in turn modulate the adhesive function of VE-cadherin are of central importance for understanding the formation of blood vessels and the regulation of the barrier function of the blood vessel system. Despite much progress in the past, elucidating the mechanistic

Acknowledgments

The work was supported in part by the Associazione Italiana per la Ricerca sul Cancro and “Special Program Molecular Clinical Oncology 5×1000” to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative) and by the European Research Council, the European Community Networks (EUSTROKE-contract-202213, OPTISTEM-contract-223098, ANGIOSCAFF-NMP3-LA-2008-214402 Networks; ENDOSTEM-HEALTH-2009-241440 and JUSTBRAIN-HEALTH-2009-241861), the Italian Ministry of University and Research, the Cariplo

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Chapter Six - The Role of VE-Cadherin in Vascular Morphogenesis and Permeability Control

Abstract

Introduction

Section snippets

Structural Properties of VE-Cadherin

General characteristics of VE-cadherin signaling

VE-Cadherin and N-Cadherin Cross Talk

Tyrosine phosphorylation of the VE-cadherin–catenin complex

Conclusions

Acknowledgments

Trends Cell Biol

Dev Cell

Trends Cell Biol

Cell

Int Rev Cell Mol Biol

Biochim Biophys Acta

Cell

J Biol Chem

J Mol Biol

J Mol Biol

J Mol Biol

Curr Opin Cell Biol

Dev Cell

Cell

Semin Cell Dev Biol

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

Dev Cell

Dev Cell

Am J Pathol

J Biol Chem

Blood

J Biol Chem

Differentiation

Cell

Cell

Blood

Mol Cell

J Biol Chem

Blood

Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis

Physiol Rev

Breaching multiple barriers: leukocyte motility through venular walls and the interstitium

Nat Rev Mol Cell Biol

Regulation of endothelial permeability via paracellular and transcellular transport pathways

Annu Rev Physiol

Current concepts of blood-brain barrier development

Int J Dev Biol

Functionally specialized junctions between endothelial cells of lymphatic vessels

J Exp Med

Spontaneous assembly and active disassembly balance adherens junction homeostasis

Proc Natl Acad Sci USA

Structural basis of cell-cell adhesion by cadherins

Nature

C-cadherin ectodomain structure and implications for cell adhesion mechanisms

Science

Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography

EMBO J

Control of endothelial barrier function by regulating vascular endothelial-cadherin

Curr Opin Hematol

Organization and signaling of endothelial cell-to-cell junctions in various regions of the blood and lymphatic vascular trees

Cell Tissue Res

CCM1 regulates vascular-lumen organization by inducing endothelial polarity

J Cell Sci

Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5

Nat Cell Biol

The cadherins: cell-cell adhesion molecules controlling animal morphogenesis

Development

The role of wnt signaling in physiological and pathological angiogenesis

Circ Res

Junctional music that the nucleus hears: cell-cell contact signaling and the modulation of gene activity

Cold Spring Harb Perspect Biol

The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin)

J Cell Biol

VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF

J Exp Med

Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin

J Cell Biol