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Published on: February 12, 2021
Vitamin D promotes vascular regeneration
Michael Sze Ka Wong1, Matthias S Leisegang1, Christoph Kruse1
1From the Institute for Cardiovascular Physiology (M.S.K.W., M.S.L., C.K., J.V., C.S., K.S., R.P.B.), Institute of Biochemistry I (N.D., A.W., B.B.), Institute for Biostatistics and Mathematical Modeling (E.H.), Institute of Pharmaceutical Chemistry/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (D.S.), Goethe University, Frankfurt, Germany; German Center for Cardiovascular Research, Partner Site RheinMain, Frankfurt, Germany (M.S.L., C.K., C.S., E.H., S.O., K.S., R.P.B.); Cardiovascular Division, King's College London British Heart Foundation Center of Excellence, London, United Kingdom (A.M.S.); Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.); Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium (G.C.); and Department of Endocrinology and Diabetes, Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany (K.B.).
Insights
Vitamin D3 (1,25-VitD3) promotes vascular regeneration by increasing angiogenic myeloid cells. This vitamin D metabolite enhances healing after injury by inducing SDF1, offering a novel therapeutic approach for vascular repair.
Area of Science:
- Cardiovascular biology
- Endocrinology
- Regenerative medicine
Background:
- Vitamin D deficiency is common and linked to inflammation and cardiovascular disease.
- The role of 1,25-dihydroxy-vitamin D3 (1,25-VitD3) in the cardiovascular system is debated, with potential for both harm (calcification) and benefit (anti-inflammatory).
- A hypothesis was formed that 1,25-VitD3 aids vascular repair after injury.
Purpose of the Study:
- To investigate the potential of 1,25-VitD3 in promoting vascular regeneration after injury.
- To elucidate the mechanisms by which 1,25-VitD3 influences vascular healing.
Main Methods:
- Supplementation with vitamin D3 in healthy volunteers and 1,25-VitD3 in mice models of vascular injury (carotid artery, femoral artery ligation).
- Assessment of angiogenic myeloid cells, reendothelialization, and angiogenesis.
- Investigation of the role of CXCR4, SDF1, and hypoxia-inducible factor 1-α (HIF-1α) signaling pathways.
- Utilized conditional knockout models for the vitamin D receptor in specific cell types.
Main Results:
- Vitamin D3 supplementation increased circulating angiogenic myeloid cells in humans.
- 1,25-VitD3 increased angiogenic myeloid cells and promoted reendothelialization in mouse models, including in diabetic mice with impaired angiogenesis.
- The pro-regenerative effects were dependent on SDF1/CXCR4 signaling and vitamin D receptor expression in myeloid cells.
- Mechanistically, 1,25-VitD3 upregulated HIF-1α, which in turn promoted SDF1 expression.
Conclusions:
- Vitamin D3, via 1,25-VitD3, enhances vascular repair and regeneration.
- The mechanism involves the induction of SDF1 by 1,25-VitD3 in myeloid cells, mediated by HIF-1α.
- This highlights vitamin D3 as a potential therapeutic strategy for promoting vascular healing.
Background:
Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone 1,25-dihydroxycholecalciferol (1,25-dihydroxy-vitamin D3; 1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D3 deficiency, however, has been linked to cardiovascular disease because the hormone has anti-inflammatory properties. We therefore hypothesized that 1,25-VitD3 promotes regeneration after vascular injury.
Methods And Results:
In healthy volunteers, supplementation of vitamin D3 (4000 IU cholecalciferol per day) increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells, which are thought to promote vascular regeneration. Similarly, in mice, 1,25-VitD3 (100 ng/kg per day) increased the number of angiogenic myeloid cells and promoted reendothelialization in the carotid artery injury model. In streptozotocin-induced diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the impaired angiogenesis in the femoral artery ligation model. Angiogenic myeloid cells home through the stromal cell-derived factor 1 (SDF1) receptor CXCR4. Inhibition of CXCR4 blocked 1,25-VitD3-stimulated healing, pointing to a role of SDF1. The combination of injury and 1,25-VitD3 increased SDF1 in vessels. Conditioned medium from injured, 1,25-VitD3-treated arteries elicited a chemotactic effect on angiogenic myeloid cells, which was blocked by SDF1-neutralizing antibodies. Conditional knockout of the vitamin D receptor in myeloid cells but not the endothelium or smooth muscle cells blocked the effects of 1,25-VitD3 on healing and prevented SDF1 formation. Mechanistically, 1,25-VitD3 increased hypoxia-inducible factor 1-α through binding to its promoter. Increased hypoxia-inducible factor signaling subsequently promoted SDF1 expression, as revealed by reporter assays and knockout and inhibitory strategies of hypoxia-inducible factor 1-α.
Conclusions:
By inducing SDF1, vitamin D3 is a novel approach to promote vascular repair.
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