Vascular endothelial growth factor‐A regulates collateral growth and specifies collateral density

Resistance to ischemic damage in vascular occlusive disease depends on the number of pre‐existing collaterals and their ability to grow (arteriogenesis, AR). Mechanisms specifying collateral number and capacity to grow are not well defined. VEGF is important in vascular formation and patterning during development. In adults, while VEGF is critical in angiogenesis, a role in arteriogenesis remains controversial. We examined AR in mice heterozygous for VEGF receptor‐1 (R1 +/− ) and VEGF receptor‐2 (R2 +/− ), and mice over‐ and under‐expressing VEGF‐A (VEGF Hi and VEGF Lo ). The femoral artery was ligated and mice were studied for 21 days. Analyses were blinded to genotype. Compared to WT, R2 +/− showed no deficits in any parameter measured. In contrast, R1 +/− showed less increase in adductor perfusion, less recovery of foot perfusion, less collateral enlargement, and greater ischemia. VEGF Hi had 3‐fold greater hindlimb perfusion immediately after ligation, a larger number of pre‐existing collaterals (confirmed by angiography), greater recovery of perfusion, and less ischemia. VEGF Lo had 2‐fold less hindlimb perfusion immediately after ligation, consistent with fewer collaterals, and blunted perfusion recovery. These studies suggest that VEGF mediates AR via R1. Moreover, they provide our first clue into signaling pathways, ie, VEGF, that may specify collateral density in tissues.