Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit

Vascular endothelial growth factor (VEGF) is known to play an important rol e in angiogenesis. Its place in collateral artery growth (arteriogenesis), however, is still debated. In the present study, we analyzed the expression of VEGF and its receptors (Flk-1 and Flt-1) in a rabbit model of collatera l artery growth after femoral artery occlusion. Hypoxia presents the most i mportant stimulus for VEGF expression. We therefore also investigated the e xpression level of distinct hypoxia-inducible genes (HIF-1 alpha, LDH A) an d determined metabolic intermediates indicative for ischemia (ATP, creatine phosphate, and their catabolites). We found that arteriogenesis was not as sociated with an increased expression of VEGF or the mentioned hypoxia-indu cible genes. Furthermore, the high-energy phosphates and their catabolites were entirely within normal limits. Despite the absence of an increased exp ression of VEGF and its receptors, collateral vessels increased their diame ter by a factor of 10. The speed of collateral development could be increas ed by infusion of the chemoattractant monocyte chemotactic protein-1 but no t by infusion of a 30 times higher concentration of VEGF. From these data, we conclude that under nonischemic conditions, arteriogenesis is neither as sociated with nor inducible by increased levels of VEGF and that VEGF is no t a natural agent to induce arteriogenesis in vivo.