Vascular Endothelial (VE)-Cadherin, Endothelial Adherens Junctions, and Vascular Disease

Abstract

Endothelial cell-cell adherens junctions (AJs) supervise fundamental vascular functions, such as the control of permeability and transmigration of circulating leukocytes, and the maintenance of existing vessels and formation of new ones. These processes are often dysregulated in pathologies. However, the evidence that links dysfunction of endothelial AJs to human pathologies is mostly correlative. In this review, we present an update of the molecular organization of AJ complexes in endothelial cells (ECs) that is mainly based on observations from experimental models. Furthermore, we report in detail on a human pathology, cerebral cavernous malformation (CCM), which is initiated by loss-of-function mutations in the genes that encode the three cytoplasmic components of AJs (CCM1, CCM2, and CCM3). At present, these represent a unique example of mutations in components of endothelial AJs that cause human disease. We describe also how studies into the defects of AJs in CCM are shedding light on the crucial regulatory mechanisms and signaling activities of these endothelial structures. Although these observations are specific for CCM, they support the concept that dysfunction of endothelial AJs can directly contribute to human pathologies.

Figure 1.

New interactors of endothelial adherens junctions (AJs). Recently described interactors of VE-cadherin complexes and their functions in nascent (A) and stabilized (B) endothelial AJs are represented as discussed in the text. In addition, in (A), the binding of EGF receptor kinase substrate 8 (EPS8) to the AJ complex is shown to inhibit the phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B) pathway, thus increasing VE-cadherin turnover at AJs (Giampietro et al. 2015) and maintaining dynamic AJs. Conversely, in stabilized AJs (B), the active PI3K/AKT pathway induces phosphorylation and cytoplasmic localization of the Yes-associated protein (YAP), which localizes to junctions and contributes to enhanced barrier function. As discussed in the text and shown in B, Rasip1 is required during stabilization of cell–cell contacts, but it is not necessary for their maintenance. The representation of the VE-cadherin domains interacting in trans (EC1-EC1) and in cis (EC1-EC2) are according to Harrison et al. (2011) and Brasch et al. (2012).

Figure 2.

Rho-GTPases associated with adherens junctions (AJs) control the actin cytoskeleton dynamics and junction stability in endothelial cells (ECs). Schematic representation of the interactions, activities, and regulation of the RhoGTPases, as discussed in the text. Rap1-GTP promotes linear and continuous AJs, with both inducing circumferential actin fibers and inhibiting Rho-GTP, which instead supports focal AJs and cell–cell retraction. Dashed lines indicate that some intermediate steps remain to be defined.

Figure 3.

Endothelial adherens junctions (AJs) are dismantled in human cerebral cavernoma. VE-cadherin (green) labeled EC cell–cell junctions in normal human brain vessels (white arrows). In human cerebral cavernoma from a patient with cerebral cavernous malformation (CCM), the AJs appear to be dismantled and VE-cadherin is ectopically distributed to the apical and basal surfaces (red and yellow arrows, respectively). Bottom panels show magnification of the boxed areas. Dashed lines outline the lumina. Scale bars, 100 µm and 50 µm (magnification panels).