Signaling Through CD31 Protects Endothelial Cells from Apoptosis. Transplantation 2001; 71: 457.

PECAM-1/CD31: MORE THAN JUST GLUE The monolayer of endothelial cells that comprise the vascular lumen has many important physiological functions; maintaining vascular tone and preventing inappropriate coagulation while at the same time controlling vascular permeability and leukocyte extravasation. This is not an easy task particularly when vascularized organs are under attack from “friendly fire” as in the case of chronic inflammation. Life is even more complicated during angiogenesis (the formation of capillaries from preexisting blood vessels) because the angiogenic programme requires endothelial cells to acquire an altered phenotype, modify cell-cell contacts, migrate, and re-establish cell-cell contacts to reform a patent tube. However, the real catch-22 for endothelial cells occurs during inflammatory episodes when endothelial cells are placed in a real dilemma. In this situation endothelial cells are exposed to many pro-apoptotic insults including tumor necrosis factor-α, and the transmigration of many activated leucocytes and yet not only must endothelial cells resist the apoptotic insult, but often need to switch on their angiogenic program to support the inflammatory response. A potential explanation for the apparent conundrum has come from two recent reports (1, 2). In this issue of Transplantation, Evans et al. show that an abundantly expressed endothelial molecule, CD31/PECAM-1, which is expressed at up to 1 million copies per cell, protects HUVEC from apoptosis induced by growth factor withdrawal. It does this through the up-regulation molecules that are known to protect endothelial cells from apoptosis (A1, A20). CD31/PECAM-1 is a 130-Kd, six domain containing member of the immunoglobulin gene superfamily, expressed on platelets, endothelial cells, monocytes, neutrophils, and subsets of lymphocytes. CD31 exists as a dimer and is able to self-associate through interdigitation of extracellular domains 1 and 2. Although the presence of CD31 on endothelial cells is not essential for the development of the vascular tree (CD31-deficient mice develop normally) CD31 does appear to play an important role in regulating the transendothelial migration of CD31 positive monocytes and neutrophils (3). Recent work has established that in addition to its role as a homophilic adhesion molecule, CD31 acts as a signaling molecule on leucocytes. For example, tyrosine and threonine residues in the cytoplasmic tail of CD31 are phosphorylated by Src and PKC family kinases leading to the recruitment of several cytoplasmic signaling and adaptor molecules including the protein tyrosine phosphatases SHP-1/2 as well as β-catenin. Signaling through CD31 has been found to activate integrins and for leucocytes to influence adhesion, proliferation as well as the production of several cytokines, and chemokines possibly via activation of the small GTPase RAP-1 (4). In contrast in endothelial cells the consequences of CD31 signaling are poorly understood. Two previous studies have suggested that engagement of CD31 on endothelial cells confer protection from apoptosis but the mechanism for this has remained obscure. Now Evans et al. have provided a potential mechanism for this (Fig. 1) which provides an exciting explanation for the role of CD31 homophilic interactions during transendothelial migration; namely, protection of endothelial cells from apoptosis. Figure 1: Stimulated endothelial cells activate NF-κb leading to the simultaneous activation of pro-inflammatory and pro-survival programs. NF-κb stimulates enhanced production of CD31 and osteoprotegerin. Ligation of CD31 leads to stimulation of the pro-survival factors A1 and A20. Ligation of the integrin αvβ3 further reenforces this cycle. Recently CD31 and avb3 have been shown to interact in cis within the same cell membrane.The findings of Evans et al. become even more intriguing given results from Malyankar et al. (2). Because initial observations that the integrin αvβ3 could be detected on growing but not quiescent blood vessels, a number of studies have directly implicated this integrin in angiogenesis and embryonic neovascularization. One of the many ligands for αvβ3, osteopontin, protects endothelial cells from apoptosis via its interaction with αvβ3 and subsequent activation of the transcription factor NF-κB. NF-κB is pleotropic regulator of many genes involved in immune and inflammatory responses. It is capable of inducing many proinflammatory genes as well as playing an important role in cell survival. It has been hypothesized that NF-κB-induced transcription of antiapoptotic genes is responsible for its protective activity. To find NF-κB-dependent genes involved in endothelial cell survival, Malyankar et al. (2) used a suppressive subtractive hybridization method to isolate genes that required active NF-κB for endothelial cell survival. In addition to genes that have previously been shown to be regulated by NF-κB and involved in endothelial inflammatory process (VCAM-1 iNOS), this screen also identified CD31 and osteoprotegerin, a new member of the tumor necrosis factor receptor superfamily which is required for osteoclast differentiation and blocks TRAIL-mediated apotosis. The finding that osteoprotegerin plays a role in endothelial survival is extremely exciting particularly because the loss of osteoprotegerin in knockout mice leads to extensive vascular inflammation and calcification in addition to severe osteoporosis. However, the identification of CD31 as an additional survival gene induced by NF-κB under conditions of growth factor deprivation is fully consistent with the findings of Evans et al. (1) A final twist is the observation that CD31 appears to physically associate with the integrin αvβ3 on the surface of leukocytes. Although this has not been demonstrated in endothelium it is tempting to speculate that CD31 acts as a signaling relay post to augment αvβ3-mediated protection from apoptosis during leukocyte transendothelial migration. In fact a wide variety of stressful stimuli including shear stress, hypoxia, TNF-α, and vascular endothelial growth factor in addition to monocyte transmigration all induce endothelial CD31 tyrosine phosphorylation. It is therefore possible that activation of CD31 under conditions of inflammatory leukocyte transmigration confers a protective signal via protective genes such as A1 and A20. The finding that these same molecules protect grafts against chronic rejection in animal models of xeno- and allo-transplantation (5) suggests that the manipulation of molecules such as CD31 and osteoprotegerin may offer real therapeutic opportunities to preempt endothelial damage in conditions such as vasculitis, atherosclerosis, and chronic rejection. However, these studies also suggest that strategies that aim to inhibit endothelial proinflammatory gene expression through blockade of NF-κB may also cause the endothelium to switch off its pro-survival genes, in effect cutting off its nose to spite its face.

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