Microvascular function after treatment with an angiogenic factor, TP508, in a porcine model of chronic ischemia

Abstract

Therapeutic angiogenesis is a new treatment modality thought to increase blood flow to ischemic areas of myocardium. The objective of this study was to determine if an experimental angiogenic factor, Chysalin® (TP508), enhances the vasodilatory function of microvessels in ischemic myocardium treated with TP508, (treated, TR) when compared to untreated ischemic myocardium (non-treated, NT) and non-ischemic myocardium from control pigs (CON). Adult Yucatan miniature swine were subjected to chronic occlusion of the left circumflex coronary artery (LCX) using an ameroid constrictor. After 28 days, either Pluronic gel (NT, n = 3) or Pluronic gel containing 150 mg of TP508 (TR, n = 8) was injected into the ischemic myocardium. Sixty days after ameroid placement, coronary arterioles (70-100 []m) were isolated from the LCX (ischemic, IS) region and LAD (non-ischemic, NIS) region of the myocardium of TR and NT pigs. Coronary arterioles were isolated from normal myocardium of non-occluded (non-ischemic) pigs and used as controls (n = 5). Microvessels were then tested for functional analysis using the vasodilators adenosine, serotonin, pinacidil, and nitroprusside. Coronary arterioles (100-300 []m in diameter) were isolated for nitric oxide (NO) analysis and eNOS gene expression using an RT/PCR technique. In our study, smooth muscle relaxation of coronary microvessels was significantly decreased in the IS region of NT animals compared to controls when assayed with adenosine and serotonin (p < 0.05), but no difference existed between CON and TR groups (p>0.05). With nitroprusside and pinacidil, no differences in dilation were observed between the three groups, suggesting a lack of endothelial NO-mediated dilation in the IS/NT group. Treated microvessels isolated for NO analysis showed a significant increase in NO production as compared to the IS/NT group (p < 0.05). Endothelial nitric oxide synthase (eNOS) mRNA expression was not significantly different between groups, suggesting that TP508-associated increase in NO in IS myocardium occurs by some mechanism other than increased eNOS expression. Results of this study suggest that TP508 treatment of ischemic myocardium results in significantly enhanced coronary microvascular vasodilation when compared to IS/NT myocardium.