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Nasim Jamali, Shoujian Wang, Soesiawati Darjatmoko, Christine Sorenson, Nader Sheibani; 1α, 25(OH)2D3 Promotes Vascular Maturation through Vitamin D Receptor Mediated VEGF Production and Attenuation of Pericyte Proliferation and Migration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5487.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular neovascularization is linked to pathogenesis of many eye diseases. We previously showed that 1α, 25(OH)2D3, the active form of vitamin D, is a potent inhibitor of angiogenesis. The action of vitamin D is mainly mediated through the vitamin D receptor (Vdr). Here we investigated whether Vdr expression impacts retinal vascular development and attenuation of neovascularization by 1α, 25(OH)2D3.
The impact of Vdr expression on retinal vasculature development and neovascularization during oxygen-induced ischemic retinopathy (OIR) was examined using wild type (Vdr +/+) and Vdr-deficient (Vdr -/-) mice. We also determined whether inhibition of retinal neovascularization by 1α, 25(OH)2D3 was Vdr-dependent. Also, using retinal pericytes (PC) and endothelial cells (EC), we assessed the expression of Vdr and their response to 1α, 25(OH)2D3.
No significant effect on postnatal retinal vascularization in Vdr -/- mice up to postnatal day 21 (P21), when the formation of primary vasculature is complete, was observed. However, we did observe a significant decrease in the ratio of EC to PC in retinas from P42 Vdr -/- mice. This was attributed to an increased number of PC in Vdr -/- mice. We observed that inhibition of retinal neovascularization by 1α, 25(OH)2D3 was Vdr dependent, even though Vdr deficiency did not significantly affect vessel obliteration and retinal neovascularization during OIR. We also found retinal PC in culture expressed a significantly higher Vdr level compared with EC. PC incubated with 1α, 25(OH)2D3 showed decreased proliferation and migration, unlike EC. These results are consistent with the increased PC number observed in the developing retinal vasculature of Vdr -/- mice. Mechanistically, incubation of Vdr +/+ PC with 1α, 25(OH)2D3 in culture resulted in increased production of vascular endothelial growth factor (VEGF), while antagonism of VEGF signaling restored PC proliferation and migration inhibited by 1α, 25(OH)2D3. We propose Increased VEGF production promotes the heterodimerization of VEGF and PDGF receptors in PC attenuating their proliferation and migration.
These studies establish an important role for vitamin D and Vdr during maturation of the developing vasculature by promoting the PC quiescence and attenuation of proangiogenic activity.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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