Targeting beta 1-integrin inhibits vascular leakage in endotoxemia

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http://hdl.handle.net/10138/304366

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Hakanpaa , L , Kiss , E A , Jacquemet , G , Miinalainen , I , Lerche , M , Guzman , C , Mervaala , E , Eklund , L , Ivaska , J & Saharinen , P 2018 , ' Targeting beta 1-integrin inhibits vascular leakage in endotoxemia ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 115 , no. 28 , pp. E6467-E6476 . https://doi.org/10.1073/pnas.1722317115

Title: Targeting beta 1-integrin inhibits vascular leakage in endotoxemia
Author: Hakanpaa, Laura; Kiss, Elina A.; Jacquemet, Guillaume; Miinalainen, Ilkka; Lerche, Martina; Guzman, Camilo; Mervaala, Eero; Eklund, Lauri; Ivaska, Johanna; Saharinen, Pipsa
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Eero Mervaala / Principal Investigator
University of Helsinki, Medicum
Date: 2018-07-10
Language: eng
Number of pages: 10
Belongs to series: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
URI: http://hdl.handle.net/10138/304366
Abstract: Loss of endothelial integrity promotes capillary leakage in numerous diseases, including sepsis, but there are no effective therapies for preserving endothelial barrier function. Angiopoietin-2 (ANGPT2) is a context-dependent regulator of vascular leakage that signals via both endothelial TEK receptor tyrosine kinase (TIE2) and integrins. Here, we show that antibodies against beta 1-integrin decrease LPS-induced vascular leakage in murine endotoxemia, as either a preventative or an intervention therapy. beta 1-integrin inhibiting antibodies bound to the vascular endotheliumin vivo improved the integrity of endothelial cell-cell junctions and protected mice from endotoxemia-associated cardiac failure, without affecting endothelial inflammation, serum proinflammatory cytokine levels, or TIE receptor signaling. Moreover, conditional deletion of a single allele of endothelial beta 1-integrin protected mice from LPS-induced vascular leakage. In endothelial mono-layers, the inflammatory agents thrombin, lipopolysaccharide (LPS), and IL-1 beta decreased junctional vascular endothelial (VE)-cadherin and induced actin stress fibers via beta 1- and alpha 5-integrins and ANGPT2. Additionally, beta 1-integrin inhibiting antibodies prevented inflammation-induced endothelial cell contractility and monolayer permeability. Mechanistically, the inflammatory agents stimulated ANGPT2-dependent translocation of alpha 5 beta 1-integrin into tensin-1-positive fibrillar adhesions, which destabilized the endothelial monolayer. Thus, beta 1-integrin promotes endothelial barrier disruption during inflammation, and targeting beta 1-integrin signaling could serve as a novel means of blocking pathological vascular leak.
Subject: beta 1-integrin
ANGPT2
TIE2
permeability
sepsis
ENDOTHELIAL-CELLS
INTEGRIN
ANGIOGENESIS
ALPHA(5)BETA(1)
ANGIOPOIETIN-2
INFLAMMATION
FIBRONECTIN
ADHESION
TRANSLOCATION
PERMEABILITY
3111 Biomedicine
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