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

ABSTRACT: 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 ?-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 ?1 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 ?1-integrin activation in talin-deficient cells with a ?1-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 ?1-integrin stabilizes VE-cadherin at endothelial junctions and promotes endothelial barrier function.

SUBMITTER: Pulous FE 

PROVIDER: S-EPMC6521868 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature