Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Trio, VE-cadherin, GEF, Rac1, Endothelium, CELL-CELL ADHESION, LEUKOCYTE TRANSENDOTHELIAL MIGRATION, RHO-GEF TRIO, ACTIN POLYMERIZATION, BARRIER FUNCTION, TYROSINE PHOSPHORYLATION, VASCULAR-PERMEABILITY, ADHERENS JUNCTIONS, SMALL GTPASES, ACTIVATION, Actin Cytoskeleton, Antigens, CD, Cadherins, Capillary Permeability, Endothelial Cells, Endothelium, Vascular, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Junctions, Protein Serine-Threonine Kinases, Signal Transduction, rac1 GTP-Binding Protein, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3101 Biochemistry and cell biology

Abstract:

Endothelial cell-cell junctions maintain a restrictive barrier that is tightly regulated to allow dynamic responses to permeability-inducing angiogenic factors, as well as to inflammatory agents and adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions depends on Rho-GTPase-controlled cytoskeletal rearrangements. How the activity of Rho-GTPases is spatio-temporally controlled at endothelial adherens junctions by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing junctions based around vascular endothelial (VE)-cadherin (also known as CDH5). Trio interacts with VE-cadherin and locally activates Rac1 at adherens junctions during the formation of nascent contacts, as assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for the remodeling of junctional actin from radial into cortical actin bundles, a crucial step for junction stabilization. This promotes the formation of linear adherens junctions and increases endothelial monolayer resistance. Collectively, our data show the importance of spatio-temporal regulation of the actin cytoskeleton through Trio and Rac1 at VE-cadherin-based cell-cell junctions in the maintenance of the endothelial barrier.