VEGF/Flk-1 activity contributes to immature vascular phenotype in male β3-null mice. Two hours following intravenous injection of VEGF into adult male wild-type mice, 22% of coronary capillaries examined exhibited luminal filopodia, extended vacuoles, and/or intussusception. These characteristics following VEGF injection are of a similar frequency as observed for untreated adult male β3-null mice. When adult male β3-null mice are treated for 2 days with pharmacologic inhibitors of either Flk-1 or VEGF (but not downstream signaling molecules such as Src kinases), the frequency of immature coronary capillaries is reduced to normal levels. These findings suggest that enhanced VEGF signaling through Flk is responsible for the vascular phenotype in adult male β3-null mice. Interestingly, VEGF injection into adult female wild-type or β3-null mice did not produce the angiogenic phenotype. Data represent mean ± SE.