| First Author | Hakanpaa L | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 28 | Pages | E6467-E6476 |
| PubMed ID | 29941602 | Mgi Jnum | J:263852 |
| Mgi Id | MGI:6189010 | Doi | 10.1073/pnas.1722317115 |
| Citation | Hakanpaa L, et al. (2018) Targeting beta1-integrin inhibits vascular leakage in endotoxemia. Proc Natl Acad Sci U S A 115(28):E6467-E6476 |
| abstractText | 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 beta1-integrin decrease LPS-induced vascular leakage in murine endotoxemia, as either a preventative or an intervention therapy. beta1-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 beta1-integrin protected mice from LPS-induced vascular leakage. In endothelial monolayers, the inflammatory agents thrombin, lipopolysaccharide (LPS), and IL-1beta decreased junctional vascular endothelial (VE)-cadherin and induced actin stress fibers via beta1- and alpha5-integrins and ANGPT2. Additionally, beta1-integrin inhibiting antibodies prevented inflammation-induced endothelial cell contractility and monolayer permeability. Mechanistically, the inflammatory agents stimulated ANGPT2-dependent translocation of alpha5beta1-integrin into tensin-1-positive fibrillar adhesions, which destabilized the endothelial monolayer. Thus, beta1-integrin promotes endothelial barrier disruption during inflammation, and targeting beta1-integrin signaling could serve as a novel means of blocking pathological vascular leak. |
