R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage.
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.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. lkannan@bidmc.harvard.edu
Lakshmi
L
Kannan
Katalin
K
Kis-Toth
Kazuhisa
K
Yoshiya
To-Ha
TH
Thai
Seema
S
Sehrawat
Tanya N
TN
Mayadas
Jurandir J
JJ
Dalle Lucca
George C
GC
Tsokos
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D007365:Intercellular Junctions / Q000187:drug effects; D065666:Mesenteric Ischemia / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D015427:Reperfusion Injury / Q000517:prevention & control; D019699:Thrombospondins / Q000378:metabolism* / Q000494:pharmacology
C517523:R-spondin3 protein, mouse; D019699:Thrombospondins
junctional integrity; organ damage; permeability; tissue repair