Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen an d permeability factor that is potently angiogenic in vivo. We report here s tudies that suggest that VEGF potentiates angiogenesis in vivo and prolongs the survival of human dermal microvascular endothelial cells (HDMECs) in v itro by inducing expression of the anti-apoptotic protein Bcl-2. Growth-fac tor-enriched and serum-deficient cultures of HDMECs grown on collagen type I gels with VEGF exhibited a 4-fold and a 1.6-fold reduction, respectively, in the proportion of apoptotic cells. Enhanced HDMEC survival was associat ed with a dose-dependent increase in Bcl-2 expression and a decrease in the expression of the processed forms of the cysteine protease caspase-3. Cult ures of HDMECs transduced with and overexpressing Bcl-2 and deprived of gro wth factors showed enhanced protection from apoptosis and exhibited a twofo ld increase in cell number and a fourfold increase in the number of capilla ry-like sprouts. HDMECs overexpressing Bcl-2 when incorporated into polylac tic acid sponges and implanted into SCID mice exhibited a sustained fivefol d increase in the number of microvessels and a fourfold decrease in the num ber of apoptotic cells when examined 7 and 14 days later. These results sug gest that the angiogenic activity attributed to VEGF may be due in part to its ability to enhance endothelial cell survival by inducing expression of Bcl-2.