Targeting ?1-integrin inhibits vascular leakage in endotoxemia.

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 ?1-integrin decrease LPS-induced vascular leakage in murine endotoxemia, as either a preventative or an intervention therapy. ?1-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 ?1-integrin protected mice from LPS-induced vascular leakage. In endothelial monolayers, the inflammatory agents thrombin, lipopolysaccharide (LPS), and IL-1? decreased junctional vascular endothelial (VE)-cadherin and induced actin stress fibers via ?1- and ?5-integrins and ANGPT2. Additionally, ?1-integrin inhibiting antibodies prevented inflammation-induced endothelial cell contractility and monolayer permeability. Mechanistically, the inflammatory agents stimulated ANGPT2-dependent translocation of ?5?1-integrin into tensin-1-positive fibrillar adhesions, which destabilized the endothelial monolayer. Thus, ?1-integrin promotes endothelial barrier disruption during inflammation, and targeting ?1-integrin signaling could serve as a novel means of blocking pathological vascular leak.

SUBMITTER: Hakanpaa L 

PROVIDER: S-EPMC6048499 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature