Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Joana Amado-Azevedo, Anne-Marieke D. van Stalborch, Erik T. Valent, Kalim Nawaz, Jan van Bezu, Etto C. Eringa, Femke P. M. Hoevenaars, Iris M. de Cuyper, Peter L. Hordijk, Victor W. M. van Hinsbergh, Geerten P. van Nieuw Amerongen, Jurjan Aman*, Coert Margadant

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak.
Original languageEnglish
JournalAngiogenesis
Early online date2021
DOIs
Publication statusE-pub ahead of print - 2021

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