Hypercholesterolemia Attenuates Angiogenesis but Does Not Preclude Augmentation by Angiogenic Cytokines

Abstract

Background The impact of hyperlipidemia on collateral vessel development in vivo remains enigmatic. We sought to determine the anatomic extent and functional capacity of the collateral bed that develops in response to limb ischemia in a well characterized animal model of spontaneous hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit. We further characterized the impact of exogenous angiogenic cytokine administration on collateral vessel development and function in the same animal model. Methods and Results Weight-matched 6-month-old male homozygous WHHL (n=9) and normal New Zealand White (NZW) (n=9) rabbits underwent surgical resection of one femoral artery. Ten days later, the ischemic hindlimb was evaluated for collateral vessel formation, blood flow, and tissue damage. Collateral vasculature was less extensive among WHHL than NZW, as indicated by a significant reduction in angiographic score (0.19±0.02 versus 0.35±0.03, P <.001) and capillary density (46.4±4.1 versus 78.9±4.6/mm 2 , P <.0002). This was associated with a reduction in calf blood pressure index (9.5±3.5% versus 32.8±2.8%, P <.0001), arterial blood flow (7.5±0.6 versus 13.6±0.7 mL/min, P <.0001), and muscle perfusion index (40.1±3.2% versus 65.9±2.0%, P <.0001) and an increase in muscle necrosis (48.16±5.41% versus 25.90±3.83% negative 2,3,5-triphenyltetrazolium chloride staining, P <.004). Treatment of WHHL rabbits (n=9) with recombinant human vascular endothelial growth factor produced a statistically significant improvement in all functional as well as anatomic indices of collateral development. Conclusions Collateral vessel development associated with hindlimb ischemia in vivo is severely attenuated in an animal model of spontaneous hypercholesterolemia but nevertheless may be augmented by administration of angiogenic cytokines.