title: Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling.
abstract: To remodel endothelial cell-cell adhesion, inflammatory cytokine- and angiogenic growth factor-induced signals impinge on the vascular endothelial cadherin (VE-cadherin) complex, the central component of endothelial adherens junctions. This study demonstrates that junction remodeling takes place at a molecularly and phenotypically distinct subset of VE-cadherin adhesions, defined here as focal adherens junctions (FAJs). FAJs are attached to radial F-actin bundles and marked by the mechanosensory protein Vinculin. We show that endothelial hormones vascular endothelial growth factor, tumor necrosis factor α, and most prominently thrombin induced the transformation of stable junctions into FAJs. The actin cytoskeleton generated pulling forces specifically on FAJs, and inhibition of Rho-Rock-actomyosin contractility prevented the formation of FAJs and junction remodeling. FAJs formed normally in cells expressing a Vinculin binding-deficient mutant of α-catenin, showing that Vinculin recruitment is not required for adherens junction formation. Comparing Vinculin-devoid FAJs to wild-type FAJs revealed that Vinculin protects VE-cadherin junctions from opening during their force-dependent remodeling. These findings implicate Vinculin-dependent cadherin mechanosensing in endothelial processes such as leukocyte extravasation and angiogenesis.
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, 3584 CT, Utrecht, Netherlands. s.huveneers@hubrecht.eu
authors.forename: Stephan
authors.initials: S
authors.lastname: Huveneers
authors.forename: Joppe
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Emma
authors.initials: E
authors.lastname: Spanjaard
authors.forename: Gerard
authors.initials: G
authors.lastname: van der Krogt
authors.forename: Ilya
authors.initials: I
authors.lastname: Grigoriev
authors.forename: Anna
authors.initials: A
authors.lastname: Akhmanova
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
authors.forename: Johan
authors.initials: J
authors.lastname: de Rooij
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D013917:Thrombin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D016596:Vinculin / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D011993:Recombinant Fusion Proteins; D013917:Thrombin; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016596:Vinculin; D000099152:Cadherin 5