Vitamin D Receptor Expression is Essential for the Antiangiogenic Activity of Vitamin D

Vitamin D compounds inhibit the growth of a variety of tumors perhaps through inhibition of angiogenesis. We previously showed that the active form of vitamin D, calcitriol (1, 25‐dihydroxyvitamin D3), is a potent inhibitor of neovascularization. However, the molecular and cellular mechanisms involved remain unknown. Here we determined whether the expression of the vitamin D receptor is essential for the antiangiogenic activity of vitamin D using mice deficient in vitamin D receptor (Vdr −/−). We also determined the impact of VDR deficiency in postnatal development of retinal vasculature. Wild type (Vdr +/+), heterozygous (Vdr +/−), and null (Vdr −/−) mice were subjected to oxygen‐induced ischemic retinopathy (OIR). During OIR postnatal day 7 (P7) mice are exposed to 75% oxygen for 5 days (P12) and then brought to room air for 5 days (P17). Maximum neovascularization occurs from P12‐P17 and degree of neovascularization is assessed at P17. To determine antiangiogenic activity of vitamin D animals received a daily intraperitoneal injection of calcitriol from P12‐P17. We showed that VDR expression is essential for inhibition of neovascularization, which was most evident in the female mice. Calcitriol failed to inhibit neovascularization in Vdr −/− mice compare to Vdr +/+ or Vdr +/− mice. Furthermore Vdr −/−, unlike the Vdr +/+, continued to gain weight following calcitriol treatment. We also observed a significant effect on the density of retinal vasculature and the number and structure of major retinal arteries during normal development. Mechanistically, we showed that retinal pericytes (PC) express significantly higher level of VDR compared with retinal endothelial cells. Calcitriol also attenuated the proliferation and migration of PC, and caused G0/G1 arrest without affecting apoptosis. Together, our results demonstrate an important role for VDR expression and inhibition of neovascularization perhaps through attenuation of PC proliferation and migration. Support or Funding Information P30 EY016665, RPB, and RRF.