Abstract 3650: Vascular Endothelial Growth Factor-A Specifies Formation of Native Collaterals and Regulates Collateral Growth in Ischemia
The density of native (pre-existing) collaterals and their capacity to enlarge into large conduit arteries in ischemia (arteriogenesis) are major determinants of the severity of tissue injury in occlusive disease. Mechanisms directing arteriogenesis remain unclear. Moreover, nothing is known about how native collaterals form in healthy tissue. Evidence suggests VEGF, which is important in embryonic vascular patterning and ischemic angiogenesis, may contribute to native collateral formation and arteriogenesis. Therefore, we examined mice heterozygous for VEGF receptor-1 (VEGFR-1+/−), VEGF receptor-2 (VEGFR-2+/−), and mice over-expressing and under-expressing VEGF-A (VEGFhi/+ and VEGFlo/+). Recovery from hindlimb ischemia was followed for 21 days after femoral artery ligation. All statements below are p<0.05. Compared to wild-type mice, VEGFR-2+/− showed no deficits in recovery of hindlimb perfusion, collateral enlargement or angiogenesis, and ischemic scores were comparable. In contrast, VEGFR-1+/− showed reduced recovery of perfusion, reduce collateral enlargement and worse ischemic scores, whereas angiogenesis was comparable. Compared to wild-type mice, VEGFlo/+ had 2-fold lower perfusion immediately after ligation (suggesting fewer native collaterals which was confirmed by angiography) and blunted recovery of perfusion. VEGFhi/+ mice had 3-fold greater perfusion immediately after ligation, more native collaterals, and improved recovery of perfusion. These differences in collateral density were confirmed in the pial cerebral circulation. Compared to wild-type mice, VEGFlo/+ formed fewer and VEGFhi/+ formed more native collaterals at neonatal ages that persisted in adults. These findings indicate VEGF and VEGFR-1 are determinants of arteriogenesis. Moreover, they identify VEGF as the first signaling molecule specifying formation of native collaterals in healthy tissues.