Endothelial RIPK3 minimizes organotypic inflammation and vascular permeability in ischemia-reperfusion injury

Recent studies have revealed a link between endothelial receptor-interacting protein kinase 3 (RIPK3) and vascular integrity. During mouse embryonic development, hypoxia can trigger elevated endothelial RIPK3 that contributes to lethal vascular rupture. However, it is unknown whether RIPK3 regulate endothelial barrier function in adult vasculature under hypoxic injury conditions such as ischemia-reperfusion (I/R) injury. Here we performed inducible genetic deletion of endothelial Ripk3 ( Ripk ^iECKO ) in mice, which led to elevated vascular permeability in the small intestine and multiple distal organs after intestinal I/R injury. Mechanistically, this vascular permeability correlated with increased endothelial secretion of IL-6 and organ-specific expression of VCAM-1 and ICAM-1 adhesion molecules. Circulating monocyte depletion with clodronate liposomes reduced permeability in organs with elevated adhesion molecules, highlighting the contribution of monocyte adhesion and extravasation to Ripk ^iECKO barrier dysfunction. These results elucidate mechanisms by which RIPK3 regulates endothelial inflammation to minimize vascular permeability in I/R injury.