Generic Portal

TY - JOUR

T1 - Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity

AU - Botros, Liza

AU - Pronk, Manon C. A.

AU - Juschten, Jenny

AU - Liddle, John

AU - Morsing, Sofia K. H.

AU - van Buul, Jaap D.

AU - Bates, Robert H.

AU - Tuinman, Pieter R.

AU - van Bezu, Jan S. M.

AU - Huveneers, Stephan

AU - Bogaard, Harm Jan

AU - van Hinsbergh, Victor W. M.

AU - Hordijk, Peter L.

AU - Aman, Jurjan

PY - 2020/5/14

Y1 - 2020/5/14

N2 - 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.

AB - 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.

KW - Bosutinib

KW - Endothelial barrier function

KW - Focal adhesion

KW - MAP4K4

KW - Tyrosine kinase inhibitors

KW - Vascular permeability

UR - http://www.scopus.com/inward/record.url?scp=85084782963&partnerID=8YFLogxK

U2 - 10.1242/jcs.240077

DO - 10.1242/jcs.240077

M3 - Article

C2 - 32198280

VL - 133

JO - Journal of cell science

JF - Journal of cell science

SN - 0021-9533

IS - 9

M1 - jcs240077

ER -