July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
1,25(OH)2D3 Attenuates Retinal Angiogenesis by Inhibiting Proangiogenic Activity of Pericytes
Author Affiliations & Notes
  • Nader Sheibani
    Ophthalmology and Visual Sciences, Univ of Wisconsin-Madison, Madison, Wisconsin, United States
    Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin, United States
  • Nasim Jamali
    Ophthalmology and Visual Sciences, Univ of Wisconsin-Madison, Madison, Wisconsin, United States
  • Christine M Sorenson
    Pediatrics, University of Wisconsin, Madison, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Nader Sheibani, None; Nasim Jamali, None; Christine Sorenson, None
  • Footnotes
    Support  RPB, RRF, NH grant EY016665, EY022883, EY026078, EPA 83573701
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3260. doi:https://doi.org/
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      Nader Sheibani, Nasim Jamali, Christine M Sorenson; 1,25(OH)2D3 Attenuates Retinal Angiogenesis by Inhibiting Proangiogenic Activity of Pericytes. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3260. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We showed that the active form of vitamin D (calcitriol; 1,25(OH)2D3) is a potent inhibitor of retinal neovascularization. However, the underlying molecular and cellular mechanisms involved remained poorly understood. We previously showed that 1,25(OH)2D3 minimally affected retinal endothelial cell (EC) proliferation and migration in culture. Perivascular supporting cells including pericytes (PC) play important roles during angiogenesis, vascular maturation, and stabilization of blood vessels. How 1,25(OH)2D3 affects retinal PC proliferation and migration, and whether these effects are mediated through vitamin D receptor (Vdr), were unknown.

Methods : Retinal PC from wild type (Vdr+/+) and Vdr-deficient (Vdr-/-) mice were prepared as described by us. The impact of 1,25(OH)2D3 on proliferation, migration, adhesion, and Vdr expression of PC were determined and compared with those from Vdr-/- cells. Vdr expression was confirmed by Western blotting and qPCR analysis of cells incubated with solvent control or 1,25(OH)2D3. Vascular endothelial growth factor (VEGF) levels were determined by ELISA. The impact of VEGF and PDGF on migration of PC was determined by transwell assay. The role of VEGF in inhibition of PC migration was confirmed using VEGF antagonists, sFlt-1 and VEGF-R2 inhibitor.

Results : Retinal PC expressed significantly higher Vdr levels compared with retinal EC. 1,25(OH)2D3 significantly decreased PC proliferation and migration resulting in a G0/G1 cell cycle arrest. In contrast, 1,25(OH)2D3 did not inhibit the proliferation of Vdr-/- PC, but it did inhibit their migration. PC adhesion to various extracellular matrix (ECM) proteins and ECM production were also affected by incubation with 1,25(OH)2D3. Vdr-/- PC were more adherent compared with Vdr+/+ cells. Mechanistically, incubation of Vdr+/+ PC with 1,25(OH)2D3 resulted in increased expression of VEGF and attenuation of signaling through VEGF-R2 and PDGF-Rβ. Incubation with soluble VEGF-R1 (sFlt-1) partially reversed the effect of VEGF on Vdr+/+ PC migration. In addition, incubation of Vdr+/+ PC with VEGF or inhibition of VEGF-R2 increased Vdr expression.

Conclusions : Retinal PC are the major source of Vdr expression. Our results suggest an important role for retinal PC as a target for vitamin D and Vdr action, and attenuation of angiogenesis through a VEGF-mediated inhibition of PDGG-Rβ and VEGF-R2 autocrine signaling.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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