Genetic regulation of collateral formation, capacity for remodeling, and VEGF

Substantial variability exists in collateral density and ischemia‐induced collateral growth (arteriogenesis) among species and humans, suggesting a genetic basis for the variability. However, the underlying mechanisms are unknown. We characterized two mouse strains with striking differences in arteriogenesis, as a model system to investigate this problem. Immediately after femoral artery ligation, perfusion in the adductor collateral zone and foot were lower in BALB/c than C57BL/6, suggesting fewer pre‐existing collaterals (confirmed with angiography and immunohistochemistry). Collateral perfusion and recovery of hindlimb perfusion over 21 days were attenuated in BALB/c, associated with reduced collateral growth and angiogenesis. BALB/c also had fewer collaterals in intestine and, remarkably, almost none in the pial circulation. Arterial branching pattern also differed between strains. Moreover, VEGF‐A isoform expression was sharply reduced in BALB/c. Transgenic mice with increased VEGF‐A expression had greater collateral density and recovery of blood flow after femoral ligation. These data characterize a model system for investigating genetic determinants of collateral development in normal tissues and collateral remodeling in ischemic disease. They also provide our first clue into one pathway, ie, VEGF, specifying collateral density in tissues. Support: NIH‐NHLBI.