R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage

Abstract

Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects. permeability | tissue repair | organ damage | junctional integrity

Sphingosine 1‐Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex–Induced Vascular Injury

“…Increasing barrier function has been shown to limit inflammation in models of ischemia-reperfusion injury and several other models of acute injury [40] [41]. Although the RAR is also an acute model of inflammation, increasing barrier function to limit the number of activated neutrophils transmigrating into tissues may have long term consequences on organ function.…”

Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock

“…Kannan et al [80] found that R-spondin3 (R-spo3) can maintain the integrity of endothelial cell barriers by enhancing the junctions between endothelial cells and preserving the positions of VE-cadherin and F-actin in the cellular peripheral zone. It has been confirmed that both inflammation and apoptosis secondary to subarachnoid hemorrhage (SAH) are of significance because of increases in vascular permeability.…”

Biomimicking Platelet–Monocyte Interactions as a Novel Targeting Strategy for Heart Healing

“…Furthermore, the presence of PLPs was visibly seen in the infarct area of heart tissue sections whereas none could be detected for the plain liposomes (Figure C). At 72 h postinfarction, most of the vascular leakages at the heart were likely had been sealed, suggesting the detected PLPs had infiltrated the heart through monocyte‐mediation rather than by EPR effect.…”