Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells
The integrity of retinal endothelial cell (EC) is essential for establishing and maintaining the retinal blood barrier to ensure proper vision. Vitamin D is a hormone with known protective roles in EC function. The majority of vitamin D action is mediated through the vitamin D receptor (VDR). VDR is...
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MDPI AG
2023-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/2/335 |
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| author | Yong-Seok Song Nasim Jamali Christine M. Sorenson Nader Sheibani |
| author_facet | Yong-Seok Song Nasim Jamali Christine M. Sorenson Nader Sheibani |
| author_sort | Yong-Seok Song |
| collection | DOAJ |
| description | The integrity of retinal endothelial cell (EC) is essential for establishing and maintaining the retinal blood barrier to ensure proper vision. Vitamin D is a hormone with known protective roles in EC function. The majority of vitamin D action is mediated through the vitamin D receptor (VDR). VDR is a nuclear receptor whose engagement by vitamin D impacts the expression of many genes with important roles in regulation of angiogenesis and inflammation. Although many studies have investigated vitamin D-VDR action in cardiovascular protection and tumor angiogenesis, its impact on retinal EC function and regulation of ocular angiogenesis and inflammation is exceedingly limited. We previously showed calcitriol, the active form of vitamin D, is a potent inhibitor of retinal neovascularization in vivo and retinal EC capillary morphogenesis in vitro. Here, using retinal EC prepared from wild-type (<i>Vdr</i><sup>+/+</sup>) and VDR-deficient (<i>Vdr</i><sup>−/−</sup>) mice, we show that retinal EC express VDR and its expression is induced by calcitriol. The lack of VDR expression had a significant impact on endothelial cell–cell and cell–matrix interactions. <i>Vdr</i><sup>−/−</sup> retinal EC proliferated at a slower rate and were more adherent and less migratory. They also exhibited increased expression levels of inflammatory markers driven in part by sustained activation of STAT1 and NF-κB pathways and were more sensitive to oxidative challenge. These changes were attributed, in part, to down-regulation of endothelial nitric oxide synthetase, enhanced hepcidin expression, and increased intracellular iron levels. Taken together, our results indicate that VDR expression plays a fundamental role in maintaining the proper angiogenic and inflammatory state of retinal EC. |
| first_indexed | 2024-03-09T13:11:17Z |
| format | Article |
| id | doaj.art-1707305b29f048aab833474b6861d96c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T13:11:17Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-1707305b29f048aab833474b6861d96c2023-11-30T21:41:02ZengMDPI AGCells2073-44092023-01-0112233510.3390/cells12020335Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial CellsYong-Seok Song0Nasim Jamali1Christine M. Sorenson2Nader Sheibani3Departments of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADepartments of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USAMcPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADepartments of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USAThe integrity of retinal endothelial cell (EC) is essential for establishing and maintaining the retinal blood barrier to ensure proper vision. Vitamin D is a hormone with known protective roles in EC function. The majority of vitamin D action is mediated through the vitamin D receptor (VDR). VDR is a nuclear receptor whose engagement by vitamin D impacts the expression of many genes with important roles in regulation of angiogenesis and inflammation. Although many studies have investigated vitamin D-VDR action in cardiovascular protection and tumor angiogenesis, its impact on retinal EC function and regulation of ocular angiogenesis and inflammation is exceedingly limited. We previously showed calcitriol, the active form of vitamin D, is a potent inhibitor of retinal neovascularization in vivo and retinal EC capillary morphogenesis in vitro. Here, using retinal EC prepared from wild-type (<i>Vdr</i><sup>+/+</sup>) and VDR-deficient (<i>Vdr</i><sup>−/−</sup>) mice, we show that retinal EC express VDR and its expression is induced by calcitriol. The lack of VDR expression had a significant impact on endothelial cell–cell and cell–matrix interactions. <i>Vdr</i><sup>−/−</sup> retinal EC proliferated at a slower rate and were more adherent and less migratory. They also exhibited increased expression levels of inflammatory markers driven in part by sustained activation of STAT1 and NF-κB pathways and were more sensitive to oxidative challenge. These changes were attributed, in part, to down-regulation of endothelial nitric oxide synthetase, enhanced hepcidin expression, and increased intracellular iron levels. Taken together, our results indicate that VDR expression plays a fundamental role in maintaining the proper angiogenic and inflammatory state of retinal EC.https://www.mdpi.com/2073-4409/12/2/335vitamin Dretinal vasculatureinflammationSTAT1eNOSNF-κB |
| spellingShingle | Yong-Seok Song Nasim Jamali Christine M. Sorenson Nader Sheibani Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells Cells vitamin D retinal vasculature inflammation STAT1 eNOS NF-κB |
| title | Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells |
| title_full | Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells |
| title_fullStr | Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells |
| title_full_unstemmed | Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells |
| title_short | Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells |
| title_sort | vitamin d receptor expression limits the angiogenic and inflammatory properties of retinal endothelial cells |
| topic | vitamin D retinal vasculature inflammation STAT1 eNOS NF-κB |
| url | https://www.mdpi.com/2073-4409/12/2/335 |
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