Abstract 3651: Caloric Restriction Stimulates Ischemia-induced Angiogenesis through an eNOS-dependent Pathway

Abstract

Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, little is known about the role of CR in the process of ischemia-induced vascular remodeling. Here, we investigated whether CR regulates angiogenic responses in vivo employing the hindlimb model of ischemia-induced angiogenesis. Wild-type (WT), endothelial nitric oxide synthase deficient (eNOS-KO) or adiponectin deficient (APN-KO) mice were randomly divided into 2 groups that were fed either ad libitum (AL) or CR (65% of the diet consumption of AL). Four weeks later, mice were subjected to unilateral hindlimb surgery. Serum adiponectin levels were measured by ELISA. The expression and activation of eNOS were assessed by Western blot analysis. Body weight of WT mice fed CR (CR-WT) was decreased by 26% compared to WT mice fed AL (AL-WT). Angiogenic repair of ischemic hindlimb was accelerated in CR-WT compared with AL-WT as evaluated by laser Doppler blood flow (p<0.05) and capillary density analyses (p<0.05). In WT mice, CR significantly enhanced ischemia-induced increase in eNOS activation of muscle tissues and increased serum adiponectin levels. In eNOS-KO mice, CR significantly increased serum adiponectin levels but did not enhance limb perfusion after surgery. In APN-KO mice, ischemia induction did not increase eNOS activation in muscle tissues, and CR had no effects on blood flow recovery and eNOS activation in ischemic limb. Our observation indicates that CR can promote angiogenesis in response to tissue ischemia through its ability to increase eNOS activation that is possibly mediated by adiponectin.