Targeting ß1-integrin inhibits vascular leakage in endotoxemia.
Proc Natl Acad Sci U S A
; 115(28): E6467-E6476, 2018 07 10.
Article
em En
| MEDLINE
| ID: mdl-29941602
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 ß1-integrin decrease LPS-induced vascular leakage in murine endotoxemia, as either a preventative or an intervention therapy. ß1-integrin inhibiting antibodies bound to the vascular endothelium in 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 ß1-integrin protected mice from LPS-induced vascular leakage. In endothelial monolayers, the inflammatory agents thrombin, lipopolysaccharide (LPS), and IL-1ß decreased junctional vascular endothelial (VE)-cadherin and induced actin stress fibers via ß1- and α5-integrins and ANGPT2. Additionally, ß1-integrin inhibiting antibodies prevented inflammation-induced endothelial cell contractility and monolayer permeability. Mechanistically, the inflammatory agents stimulated ANGPT2-dependent translocation of α5ß1-integrin into tensin-1-positive fibrillar adhesions, which destabilized the endothelial monolayer. Thus, ß1-integrin promotes endothelial barrier disruption during inflammation, and targeting ß1-integrin signaling could serve as a novel means of blocking pathological vascular leak.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Integrina beta1
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Endotoxemia
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Células Endoteliais
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Junções Intercelulares
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Finlândia