Key result
Targeting β1-integrin with inhibitory antibodies significantly decreased LPS-induced vascular leakage and protected mice from endotoxemia-associated cardiac failure.
Targeting β1-integrin signaling reduces pathological vascular leak and protects against endotoxemia-associated cardiac failure in preclinical models.
β1-integrin inhibition may mitigate sepsis-related vascular leak; leaves open translation to human therapy.
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 β1-integrin decrease LPS-induced vascular leakage in murine endotoxemia, as either a preventative or an intervention therapy. β1-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 β1-integrin protected mice from LPS-induced vascular leakage. In endothelial monolayers, the inflammatory agents thrombin, lipopolysaccharide (LPS), and IL-1β decreased junctional vascular endothelial (VE)-cadherin and induced actin stress fibers via β1- and α5-integrins and ANGPT2. Additionally, β1-integrin inhibiting antibodies prevented inflammation-induced endothelial cell contractility and monolayer permeability. Mechanistically, the inflammatory agents stimulated ANGPT2-dependent translocation of α5β1-integrin into tensin-1-positive fibrillar adhesions, which destabilized the endothelial monolayer. Thus, β1-integrin promotes endothelial barrier disruption during inflammation, and targeting β1-integrin signaling could serve as a novel means of blocking pathological vascular leak.
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Hakanpää et al. (2018) studied Endotoxemia and Vascular Leakage. β1-integrin inhibiting antibody vs. Control antibody was evaluated on Vascular leakage. Targeting β1-integrin with inhibitory antibodies significantly decreased LPS-induced vascular leakage and protected mice from endotoxemia-associated cardiac failure.