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

Liza Botros, Manon C A Pronk, Jenny Juschten, John Liddle, Sofia K S 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 Hinsbergh, Peter L Hordijk, Jurjan Aman

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims: Endothelial barrier dysfunction leads to edema and vascular leak, carrying high morbidity and mortality. Previously, Abl kinase inhibition was 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.Methods & Results: Bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented 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 signals via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Arg by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation.Conclusion: MAP4K4 was identified as important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell-cell junctions during inflammation. Inhibiting both Arg and MAP4K4, the clinically available drug bosutinib may form a viable strategy against vascular leakage syndromes.

Original languageEnglish
Article numberjcs240077
JournalJournal of Cell Science
Volume133
Issue number9
DOIs
Publication statusE-pub ahead of print - 20 Mar 2020

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