PECAM-1 (CD31) function

Angiogenesis, the formation of new blood vessels from preexisting ones, is a complex process consisting of interrelationships of angiogenic, survival and differentiation factors and their receptors with cell adhesion and cell-matrix adhesion molecules (Beck and D’Amore, 1997; Folkman and D’Amore, 1996; Hanahan, 1997; Hanahan and Folkman, 1996; Risau, 1997; Sage, 1997; Stromblad and Cheresh, 1996). During the first step of angiogenesis, cell-cell junctions become looser, enabling cell migration and invasion through the underlying and surrounding matrix. This is followed by cell proliferation, matrix deposition and formation of stable cell-cell contacts. These activities are strictly controlled to ensure normal development of blood vessels. Among the various peptide growth factors that participate in the regulation of angiogenesis, VEGF appears to play a pivotal role in the regulation of normal and abnormal angiogenesis. VEGF is a multi-functional protein affecting endothelial cell proliferation (Conn et al., 1990; Leung et al., 1989; Plouet et al., 1989), migration (Abedi and Zachary, 1997) and permeability (Keck et al., 1989; Connolly et al., 1989; Senger et al., 1983). The latter has recently been shown to be mediated by disruption of cell-cell junctions (Kevil et al., 1998). In addition, VEGF was demonstrated to be an endothelial cell survival factor in both in vitro (Ilan et al., 1998) and in vivo models (Alon et al., 1995; Benjamin and Keshet, 1997). This is in agreement with VEGF expression around normal quiescent microvessels, suggesting that VEGF may be required for the maintenance of the differentiated state of blood vessels (Ferrara and Davis-Smyth, 1997). The continuous exposure of endothelial cells to a strong mitogen such as VEGF, on one hand and endothelial cell stability on the other hand suggests the presence of specific mechanism(s) that regulate the activities of selected multifunctional proteins including catenins. In this report we provide evidence that VEGF induces βcatenin tyrosine phosphorylation. We also demonstrate that platelet endothelial cell adhesion molecule (PECAM-1) functions as a reservoir for and also a modulator of tyrosinephosphorylated β-catenin, suggesting that PECAM-1 functions as a dynamic modulator of vascular endothelial cell behavior and may serve as a paradigm for similar functioning molecules in other cell types.