1 alpha,25-dihydroxyvitamin D-3 inhibits angiogenesis in vitro and in vivo

Modulation of angiogenesis is now a recognized strategy for the prevention and treatment of pathologies categorized by their reliance on a vascular su pply. The purpose of this study was to evaluate the effect of 1 alpha,25-di hydroxyvitamin D-3 [1,25(OH)(2)D-3], the active metabolite of vitamin D-3, on angiogenesis by using well-charaeterized in vitro and in vivo model syst ems. 1,25(OH)(2)D-3 (1x10(-9) to 1x10(-7) mol/L) significantly inhibited va scular endothelial growth factor (VEGF)-induced endothelial cell sprouting and elongation in vitro in a dose-dependent manner and had a small, but sig nificant, inhibitory effect on VEGF-induced endothelial cell proliferation. 1,25(OH)(2)D-3 also inhibited the formation of networks of elongated endot helial cells within 3D collagen gels. The addition of 1,25(OH)(2)D-3 to end othelial cell cultures containing sprouting elongated cells induced the reg ression of these cells, in the absence of any effect on cells present in th e cobblestone monolayer. Analysis of nuclear morphology, DNA integrity, and enzymatic in situ labeling of apoptosis-induced strand breaks demonstrated that this regression was due to the induction of apoptosis specifically wi thin the sprouting cell population. The effect of 1,25(OH)(2)D-3 on angioge nesis in vivo was investigated by using a model in which MCF-7 breast carci noma cells, which had been induced to overexpress VEGF, were xenografted su bcutaneously together with MDA-435S breast carcinoma cells into nude mice. Treatment with 1,25(OH)(2)D-3 (12.5 pmol/d for 8 weeks) produced tumors tha t were less well vascularized than tumors formed in mice treated with vehic le alone. These results highlight the potential use of 1,25(OH)(2)D-3 in bo th the prevention and regression of conditions characterized by pathologica l angiogenesis.