Abstract
Vitamin D provides a significant benefit to human health, and its deficiency has been linked to a variety of diseases including cancer. Vitamin D exhibits anticancer effects perhaps through inhibition of angiogenesis. We previously showed that the active form of vitamin D (1, 25(OH)2D3; calcitriol) is a potent inhibitor of angiogenesis in mouse model of oxygen-induced ischemic retinopathy (OIR). Many of vitamin D’s actions are mediated through vitamin D receptor (VDR). However, the role VDR expression plays in vascular development and inhibition of neovascularization by 1, 25(OH)2D3 remains unknown. Here using wild type (Vdr +/+) and Vdr-deficient (Vdr -/-) mice, we determined the impact of Vdr expression on postnatal development of retinal vasculature and retinal neovascularization during OIR. We observed no significant effect on postnatal retinal vascular development in Vdr -/- mice up to postnatal day 21 (P21) compared with Vdr +/+ mice. However, we observed an increase in density of pericytes (PC) and a decrease in density of endothelial cells (EC) in P42 Vdr -/- mice compared with Vdr +/+ mice, resulting in a significant decrease in the EC/PC ratio. Although we observed no significant impact on vessel obliteration and retinal neovascularization in Vdr -/- mice compared with Vdr +/+ mice during OIR, the VDR expression was essential for inhibition of retinal neovascularization by 1, 25(OH)2D3. In addition, the adverse impact of 1, 25(OH)2D3 treatment on the mouse bodyweight was also dependent on VDR expression. Thus, VDR expression plays a significant role during retinal vascular development, especially during maturation of retinal vasculature by promoting PC quiescence and EC survival, and inhibition of ischemia-mediated retinal neovascularization by 1, 25(OH)2D3.
Highlights
Vitamin D Receptor (VDR) is a member of the nuclear transcription factor superfamily
These results indicated no significant difference in the mean number of tip cell sprouts in vitamin D receptor (Vdr) -/- mice compared with Vdr +/- and Vdr +/+ littermates (Fig 1B)
Our data demonstrated no significant changes in endothelial cells (EC)/PC ratio in retinal vasculature of postnatal day 21 (P21) Vdr -/- mice compared with Vdr +/+ mice (Fig 4B)
Summary
Vitamin D Receptor (VDR) is a member of the nuclear transcription factor superfamily. Through activation by vitamin D, VDR could associated with other nuclear transcription factors including retinoid-X-receptor (RXRα) and binds to the vitamin D response element in target genes causing expression or transrepression [1, 2]. The majority of vitamin D action is believed to be mediated through VDR. Genetic variation in VDR could lead to vitamin D deficiency, which is associated with increased risk for cancer and a variety of other diseases. VDR is detectable in almost all human tissues. VDR is detected in retinal ganglion cell layer, inner nuclear layer, retinal pigment epithelium and the epithelium of cornea, lens, ciliary body, and retinal photoreceptor cells [3, 4]
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