Talin-Dependent Integrin Activation Regulates VE-Cadherin Localization and Endothelial Cell Barrier Function.

Autor:	Pulous FE; From the Department of Pediatrics, Aflac Cancer and Blood Disorders Center (F.E.P., S.K., B.G.P.), Emory University School of Medicine, Atlanta, GA.; Cancer Biology Graduate Program (F.E.P.), Emory University School of Medicine, Atlanta, GA., Grimsley-Myers CM; Department of Cell Biology (C.M.G.-M., A), Emory University School of Medicine, Atlanta, GA., Kansal S; From the Department of Pediatrics, Aflac Cancer and Blood Disorders Center (F.E.P., S.K., B.G.P.), Emory University School of Medicine, Atlanta, GA., Kowalczyk AP; Winship Cancer Institute (A.P.K.), Emory University School of Medicine, Atlanta, GA.; Department of Dermatology (A.P.K.), Emory University School of Medicine, Atlanta, GA., Petrich BG; From the Department of Pediatrics, Aflac Cancer and Blood Disorders Center (F.E.P., S.K., B.G.P.), Emory University School of Medicine, Atlanta, GA.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2019 Mar 15; Vol. 124 (6), pp. 891-903.
DOI:	10.1161/CIRCRESAHA.118.314560
Abstrakt:	Rationale: Endothelial barrier function depends on the proper localization and function of the adherens junction protein VE (vascular endothelial)-cadherin. Previous studies have suggested a functional relationship between integrin-mediated adhesion complexes and VE-cadherin yet the underlying molecular links are unclear. Binding of the cytoskeletal adaptor protein talin to the β-integrin cytoplasmic domain is a key final step in regulating the affinity of integrins for extracellular ligands (activation) but the role of integrin activation in VE-cadherin mediated endothelial barrier function is unknown. Objective: To test the requirement of talin-dependent activation of β1 integrin in VE-cadherin organization and endothelial cell (EC) barrier function. Methods and Results: EC-specific deletion of talin in adult mice resulted in impaired stability of intestinal microvascular blood vessels, hemorrhage, and death. Talin-deficient endothelium showed altered VE-cadherin organization at EC junctions in vivo. shRNA (short hairpin RNA)-mediated knockdown of talin1 expression in cultured ECs led to increased radial actin stress fibers, increased adherens junction width and increased endothelial monolayer permeability measured by electrical cell-substrate impedance sensing. Restoring β1-integrin activation in talin-deficient cells with a β1-integrin activating antibody normalized both VE-cadherin organization and EC barrier function. In addition, VE-cadherin organization was normalized by reexpression of talin or integrin activating talin head domain but not a talin head domain mutant that is selectively deficient in activating integrins. Conclusions: Talin-dependent activation of EC β1-integrin stabilizes VE-cadherin at endothelial junctions and promotes endothelial barrier function.
Databáze:	MEDLINE
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