Targeting β1-integrin inhibits vascular leakage in endotoxemia

L Hakanpaa, EA Kiss, Guillaume Jacquemet, I Miinalainen, M Lerche, Camilo Guzman, E Mervaala, L Eklund, J Ivaska, P Saharinen

Forskningsoutput: TidskriftsbidragArtikelPeer review

38 Citeringar (Scopus)

Sammanfattning

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.
OriginalspråkOdefinierat/okänt
Sidor (från-till)
Antal sidor10
TidskriftProceedings of the National Academy of Sciences
Volym115
DOI
StatusPublicerad - 2018
MoE-publikationstypA1 Tidskriftsartikel-refererad

Nyckelord

  • beta 1-integrin
  • ANGPT2
  • TIE2
  • Sepsis

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