Vascular endothelial cadherin, VE-cadherin, mediates adhesion between endothelial cells and may affect vascular morphogenesis via intracellular signaling, but the nature of these signals remains unknown. Here, targeted inactivation (VEC-/-) or truncation of the beta-catenin-binding cytosolic domain (VECdeltaC/deltaC) of the VE-cadherin gene was found not to affect assembly of endothelial cells in vascular plexi, but to impair their subsequent remodeling and maturation, causing lethality at 9.5 days of gestation. Deficiency or truncation of VE-cadherin induced endothelial apoptosis and abolished transmission of the endothelial survival signal by VEGF-A to Akt kinase and Bcl2 via reduced complex formation with VEGF receptor-2, beta-catenin, and phosphoinositide 3 (PI3)-kinase. Thus, VE-cadherin/ beta-catenin signaling controls endothelial survival.

endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability. Journal of Cell Science 2116 paracellular permeability is governed by the opening and closing of cell junctions, which implies that a complex rearrangement of adhesion proteins and the related cytoskeleton must occur. It is likely that the two pathways are interconnected in some way, because many permeability-increasing agents increase vesicular transport and also disrupt the integrity of endothelial cell-cell junctions (Dejana, 2004;Feng et al., 1999;Weis and Cheresh, 2005); however, whether this occurs in the same vessels and at the same time is still a matter of debate. It is possible that, in some areas of the vasculature, such as the microvasculature of the glands, the transcellular pathway is better developed, whereas in others, such as the postcapillary venules, the paracellular pathway is favored. It will be of interest, once more knowledge is available on the vesicular-transport systems in endothelial cells, to try to integrate both systems into a more comprehensive picture. This Commentary focuses on the role of cell-cell junctionsparticularly adherens junctions (AJs) -in the barrier function of the endothelium. We pay particular attention to the function, molecular organization and regulation of vascular endothelial (VE)-cadherin, the endothelium-specific transmembrane component of AJs. Finally, we show that pharmacological strategies for modulating endothelial permeability can be obtained by using our knowledge of the structure and function of AJs. Adherens junctions and vascular integrityPrevious work has described the molecular organization of the different types of endothelial cell-cell junctions, and has established a basis for understanding how these structures might crosstalk and reciprocally interact (Bazzoni and Dejana, 2004;Muller, 2003;Vestweber, 2007;Wallez and Huber, 2007). Endothelial-cell junctions present a particularly complex network of adhesion proteins that are linked to intracellular cytoskeletal and signaling partners. These proteins are organized into distinct structures called tight junctions (TJs) and AJs. In addition, several adhesion proteins [such as platelet endothelial cell adhesion molecule (PECAM1), MUC18, intercellular adhesion molecule 2 (ICAM2), CD34, endoglin and others] cluster at cell-cell contacts that are distinct from TJs and AJs. There are data to suggest that the assembly of AJs is required for the correct organization of TJs, but...

SUMMARY A key function of blood vessels, to supply oxygen, is impaired in tumors because of abnormalities in their endothelial lining. PHD proteins serve as oxygen sensors and may regulate oxygen delivery. We therefore studied the role of endothelial PHD2 in vessel shaping by implanting tumors in PHD2+/− mice. Haplodeficiency of PHD2 did not affect tumor vessel density or lumen size, but normalized the endothelial lining and vessel maturation. This resulted in improved tumor perfusion and oxygenation and inhibited tumor cell invasion, intravasation, and metastasis. Haplodeficiency of PHD2 redirected the specification of endothelial tip cells to a more quiescent cell type, lacking filopodia and arrayed in a phalanx formation. This transition relied on HIF-driven upregulation of (soluble) VEGFR-1 and VE-cadherin. Thus, decreased activity of an oxygen sensor in hypoxic conditions prompts endothelial cells to readjust their shape and phenotype to restore oxygen supply. Inhibition of PHD2 may offer alternative therapeutic opportunities for anticancer therapy.

In the present paper, we characterize an antibody, mAb BV13, directed to mouse vascular endothelial (VE)-cadherin, a major adhesive protein of interendothelial adherens junctions. When added to cultured endothelial cells, BV13 induces a redistribution of VE-cadherin from intercellular junctions. VE-cadherin redistribution did not change the localization of platelet endothelial cell adhesion molecule or tight junction markers such as zonula occludens 1, cingulin, and junctional adhesion molecule. Intravenous administration of mAb BV13 induced a concentration-and timedependent increase in vascular permeability in heart and lungs. By electron microscopy, interstitial edema and accumulation of mixed types of inf lammatory cells in heart and lungs were observed. Injection of (rhodamine-labeled) Ricinus communis I lectin showed focal spots of exposed basement membrane in the alveolar capillaries and in some larger pulmonary vessels. These data indicate that VE-cadherin is required for vascular integrity and normal organ functions.