Abstract 17179: Blunted Vasoreactivity and Loss of Flow Reserve Contribute to Impaired Arteriogenesis in Diabetic Peripheral Artery Disease

Introduction: Given the uncertainty around the exact pathophysiological mechanisms of diabetic peripheral artery disease (PAD), patients continue to have extremely poor prognoses. Our study attempted to address this critical unmet need. Hypothesis: We hypothesize that vasoreactivity in the feeding artery and impaired peripheral flow reserve are two primary causes of impaired arteriogenesis in these patients. Methods: The distal right femoral artery was ligated 2 weeks after streptozocin (STZ, n=12) or citrate buffer (n=12) treatment in wild-type (WT) mice. The contralateral hindlimbs were used as a negative control. 2 weeks post-hindlimb ischemia (HLI), the endothelial (EC)-dependent and EC-independent vasodilatation of the feeding artery was investigated using a Vevo 770 preclinical ultrasound scanner. Peripheral flow reserve was also assessed by pulse wave Doppler after 60 ul adenosine (3mg/ml) was administered systemically. A microCT angiography was performed to quantify collateral arteries. Gastrocnemius muscles were taken both for immunohistochemical examination in the evaluation of angiogenesis. Results: Femoral diameters at rest were similar between both control and diabetic models. In the non-ischemic limb, diabetes markedly blunted endothelial and smooth muscle cell (SMC) vasodilation reaction in the proximal femoral artery when compared with control mice [[acetylcholine (Ach): 286.3 ±16 μm versus 370±30 μm; sodium nitroprusside (SNP): 285±24.5 μm versus 350±30 μm, p<0.01]. In the ischemic hindlimb, chronic ischemia impaired vasodilation in diabetic mice when compared with control mice (Ach: 255±16 μm versus 330±40 μm; SNP: 340±50 μm versus 253±22 μm, p<0.05). In diabetic mice, peripheral flow reserve was impaired (1.27±0.27 in controls vs 0.87±0.13 in diabetes, p<0.05), with arteriole rarefaction and increased capillary/muscle ratio. Conclusions: This study demonstrated that chronic hyperglycemia negatively affects collateral development at different levels: 1 ) dysregulation of the feeding artery; 2 ) impaired arteriogenesis and increased angiogenesis; and 3 ) loss of peripheral flow reserve.