Abstract 5571: Adiponectin Improves Angiogenic Repair of Ischemic Muscle through a COX-2 Dependent Mechanism Involving Calreticulin
Adiponectin is a fat-derived plasma protein that plays protective roles in obesity-linked diseases. Specifically, adiponectin promotes ischemia-induced blood vessel growth, but the precise mechanisms underlying these pro-angiogenic actions remain unclear. Because cyclooxygenase-2 (COX-2) has been shown to be pro-angiogenic, we investigated the possible contribution of endothelial COX-2 to adiponectin-mediated angiogenic responses using loss-and gain-of genetic manipulations in a mouse model of vascular insufficiency. Ischemic hindlimb surgery markedly increased COX-2 expression in vascular endothelial cells in muscle of wild-type mice but not adiponectin knockout (APN-KO) mice. Endothelial specific-COX-2-KO mice showed decreased blood flow recovery and reduced capillary density in ischemic hindlimbs compared with control mice. Adenovirus-mediated supplement of adiponectin stimulated COX-2 expression and angiogenic responses in ischemic limbs in control mice but not endothelial specific-COX-2-KO mice. In cultured endothelial cells, treatment with recombinant adiponectin significantly increased COX-2 expression and production of prostacyclin metabolites. Deletion of COX-2 by siRNA techniques abrogated adiponectin -induced increase in endothelial migration, differentiation into vascular-like structure and survival. Of note, adiponectin-mediated increase in COX-2 expression and pro-angiogenic responses was diminished by knockdown of a novel adiponectin receptor, calreticulin (CRT) but not other reported adiponectin receptors. In addition, ablation of an adaptor protein of CRT, CD91 also suppressed the increased COX-2 expression and pro-angiogenic responses caused by adiponectin. Our observations provide evidence that CRT mediates adiponectin-stimulated angiogenic repair of ischemic tissue which is dependent on COX-2 signaling. These data suggest that adiponectin-COX-2 regulatory axis can act as a functional link between adipose tissue and the vascular endothelium.