title: Local VE-cadherin mechanotransduction triggers long-ranged remodeling of endothelial monolayers.
abstract: In this study, we present results demonstrating that mechanotransduction by vascular endothelial cadherin (VE-cadherin, also known as CDH5) complexes in endothelial cells triggers local cytoskeletal remodeling, and also activates global signals that alter peripheral intercellular junctions and disrupt cell-cell contacts far from the site of force application. Prior studies have documented the impact of actomyosin contractile forces on adherens junction remodeling, but the role of VE-cadherin in force sensation and its ability to influence endothelial cell and tissue mechanics globally have not been demonstrated. Using mechanical manipulation of VE-cadherin bonds and confocal imaging, we demonstrate VE-cadherin-based mechanotransduction. We then demonstrate that it requires homophilic VE-cadherin ligation, an intact actomyosin cytoskeleton, Rho-associated protein kinase 1 (ROCK1) and phosphoinositide 3-kinase. VE-cadherin-mediated mechanotransduction triggered local actin and vinculin recruitment, as well as global signals that altered focal adhesions and disrupted peripheral intercellular junctions. Confocal imaging revealed that VE-cadherin-specific changes appear to propagate across cell junctions to disrupt distant inter-endothelial junctions. These results demonstrate the central role of VE-cadherin adhesions and the actomyosin cytoskeleton within an integrated, mechanosensitive network that both induces local cytoskeletal remodeling at the site of force application and regulates the global integrity of endothelial tissues.
authors: Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA Medical Scholars Program, University of Illinois, Urbana, IL 61801, USA.
authors: Adrienne K
authors: AK
authors: Barry
authors: Department of Mechanical Engineering, University of Illinois, Urbana, IL 61801, USA.
authors: Ning
authors: N
authors: Wang
authors: Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, IL 61801, USA leckband@illinois.edu.
authors: Deborah E
authors: DE
authors: Leckband
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016596:Vinculin / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D019869:Phosphatidylinositol 3-Kinases; D016596:Vinculin; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C515851:ROCK1 protein, human
keywords: Magnetic twisting cytometry; Mechanotransduction; VE-cadherin; Vinculin