1. Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation
- Author
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Femke P. M. Hoevenaars, Geerten P van Nieuw Amerongen, Jan van Bezu, Anne-Marieke D. van Stalborch, Iris M. De Cuyper, Coert Margadant, Etto C. Eringa, Jurjan Aman, Erik T. Valent, Kalim Nawaz, Victor W.M. van Hinsbergh, Peter L. Hordijk, Joana Amado-Azevedo, AII - Inflammatory diseases, ACS - Atherosclerosis & ischemic syndromes, Physiology, ACS - Microcirculation, ACS - Diabetes & metabolism, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and Medical oncology laboratory
- Subjects
0301 basic medicine ,Cancer Research ,Integrins ,RHOA ,Endothelium ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Integrin ,Inflammation ,Adherens junction ,Extracellular matrix ,03 medical and health sciences ,Mice ,0302 clinical medicine ,VE-cadherin ,Arg/Abl2 ,medicine ,Cell Adhesion ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Mice, Knockout ,Original Paper ,Vascular leak ,biology ,Chemistry ,Gap Junctions ,Endothelial barrier function ,Protein-Tyrosine Kinases ,Cell biology ,Extracellular Matrix ,Endothelial stem cell ,Enzyme Activation ,Pulmonary Alveoli ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,medicine.symptom - 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. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-021-09781-x.
- Published
- 2021