Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity

• DOI: 10.1242/jcs.240077
• Publication Date: 2020-03-20T13:39:29Z
• Authors: Liza Botros; Manon C. A. Pronk; Jenny Juschten; John Liddle; Sofia K. H. Morsing; Jaap D. van Buul; Robert H. Bates; Pieter R. Tuinman; Jan S. M. van Bezu; Stephan Huveneers; Harm Jan Bogaard; Victor W. M. van ...; Peter L. Hordijk; Jurjan Aman
• Keywords: Capillary Permeability; 0301 basic medicine; Focal Adhesions; Mice; 0303 health sciences; 03 medical and health sciences; Aniline Compounds; Pharmaceutical Preparations; Nitriles; Quinolines; Animals; Adherens Junctions; 3. Good health

ABSTRACT Endothelial barrier dysfunction leads to edema and vascular leak, causing high morbidity and mortality. Previously, Abl kinase inhibition has been shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes. We found that the inhibitor bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented lipopolysaccharide (LPS)-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, mitogen-activated protein 4 kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signaled via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Abl-related gene (Arg, also known as ABL2) by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation. We conclude that MAP4K4 is an important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell–cell junctions during inflammation. Because it inhibits both Arg and MAP4K4, use of the clinically available drug bosutinib might form a viable strategy against vascular leakage syndromes.