Vascular Endothelial-cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating Rhoa □ D Changes in Vascular Endothelial (ve)-cadherin–mediated Cell-cell Adhesion and Integrin-mediated Cell-matrix Adhesion Coordinate to Affect the Physical and Mechanical Rearrangemen

INTRODUCTION Coordinated changes between cell adhesion to the extracel-lular matrix (ECM) and to neighboring cells are crucial for the many physical transformations that cells must undergo during development, tissue homeostasis, and wound healing. In the endothelium, where a single layer of cells separates tissues from their blood supply, the concerted regulation of cell-cell and cell-ECM adhesion drives rapid changes in cell shape and vascular architecture essential to vascular remodeling in both normal and disease processes (Vestwe-ber, 2000; Dudek and Garcia, 2001). Dynamic changes in cell-cell and cell-matrix adhesion and mechanical forces are responsible for regulating vascular permeability, and agents that alter permeability invariably affect both types of adhesion complexes (Dudek and Garcia, 2001). During blood vessel sprouting and migration in angiogenesis, endothelial cells must disassemble and reform their cell-cell and cell-ECM contacts in synchrony to generate appropriate structures. These two adhesion systems each regulate their functional effects through both biochemical and mechanical signals. Changes in integrin binding to ECM not only alter signals that regulate cell proliferation, migration, and survival (As-but also modulate cell mechanics by affecting focal adhesion (FA) maturation, adhesion strength, cytoskeletal contractility, and cell shape (Geiger and Ber-shadsky, 2002; Juliano, 2002). Likewise, changes in the engagement of vascular endothelial (VE)-cadherin, the principal junctional molecule in endothelial cells (Dejana et al., 1999), alter both biochemical pathways, such as vascular endothelial growth factor (VEGF) and cell survival signaling (Carmeliet et al., 1999), as well as mechanical states by altering cytoskeletal organization and the local transfer of mechanical stress (Shay-Salit et al., 2002). Although the biochemical and mechanical consequences of integrin-and cadherin-mediated adhesion each have been described, how these adhesions cross talk and cooperate is less well understood. Although studies have reported that cell-cell cohesivity through cadherins competitively decreases cell-substratum adhesivity, a process known as contact inhibition of cell adhesion and spreading (Yap and Manley, 1993; Ryan et al., 2001), an explanation for the underlying mechanism remains elusive. Cadherin engagement between cells leads to the formation of adherens junctions, the cytoplasmic face of which consists of an adhesion plaque containing many of the same structural proteins as are found in FAs (Pokutta and Weis, 2002). VE-cadherin–mediated contact could thus affect integrin-mediated adhesion indirectly by competing for a limited pool of these shared molecules (Levenberg et al., 1998). Cadherin-mediated adhesion also directly initiates both mechanical and biochemical signals known to affect FA formation. First, mechanical stress exerted at cadherin cell Article …