Interleukin-33 protects mice against hindlimb ischemic injury by enhancing endothelial angiogenesis.

Abstract

Peripheral vascular disease usually leads to vascular injury and inflammatory reaction, and the main therapeutic measures are improving angiogenesis and restoring blood flow. Interleukin-33 (IL-33) is a pleiotropic cytokine implicated in immune responses and tissue repair. Here, we explore the effect of IL-33 in hindlimb ischemic injury and elucidate the potential mechanisms of action. The expression of IL-33 and its receptor ST2 were obviously elevated in ischemic hindlimb of mice underwent ligation surgery. Exogenous IL-33 apparently facilitated blood flow restoration in ischemic hindlimb, whereas ST2-deficient mice displayed severe defects in ischemic hindlimb repair. The activation of IL-33/ST2 signaling contributed to revascularization in ischemic hindlimb, which was related to modulation of proangiogenic function of endothelial cells. Further ex vivo and in vitro studies revealed that IL-33 clearly accelerated angiogenesis by Matrigel plug and tube formation assays. Mechanically, the angiogenic function of IL-33 is involved in regulation of Akt/eNOS pathway. All together, these findings imply that IL-33-mediated endothelial angiogenesis may represent a prospective effective therapy for hindlimb ischemic damage.