Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism

Abstract

Adiponectin is a fat-derived plasma protein that has cardioprotective roles in obesity-linked diseases. Because cyclooxygenase 2 (COX-2) is an important modulator of endothelial function, we investigated the possible contribution of COX-2 to adiponectin-mediated vascular responses in a mouse hind limb model of vascular insufficiency. Ischemic insult increased COX-2 expression in endothelial cells of wild-type mice, but this induction was attenuated in adiponectin knockout mice. Ischemia-induced revascularization was impaired in mice in which the Cox-2 gene is deleted in Tie2-Cre-expressing cells. Adenovirus-mediated overexpression of adiponectin enhanced COX-2 expression and revascularization of ischemic limbs in control mice, but not in targeted Cox-2-deficient mice. In cultured endothelial cells, adiponectin protein increased COX-2 expression, and ablation of COX-2 abrogated the adiponectin-stimulated increases in endothelial cell migration, differentiation, and survival. Ablation of calreticulin (CRT) or its adaptor protein CD91 diminished adiponectin-stimulated COX-2 expression and endothelial cell responses. These observations provide evidence that adiponectin promotes endothelial cell function through CRT/CD91-mediated increases in COX-2 signaling. Thus, disruption of the adiponectin-COX-2 regulatory axis in endothelial cells could participate in the pathogenesis of obesity-related vascular diseases.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We gratefully acknowledge the technical assistance of Mina Sonoda.

This work was supported by NIH National Heart, Lung, and Blood Institute grant NO1-HV-28178 and by other grants from the NIH (AG15052, HL86785, HL91949, and HL81587) to K.W. N.O. was supported in part by an American Heart Association Scientist Development Grant, Northeast Affiliate, and K.O. was supported by the Manpei Suzuki Diabetes Foundation.