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Reviews in Cardiovascular Medicine  2020, Vol. 21 Issue (3): 339-344     DOI: 10.31083/j.rcm.2020.03.131
Special Issue: Utilizing Technology in the COVID 19 era
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Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19
Jun Zhang1, *(), Peter A. McCullough1, 2, 3, Kristen M. Tecson1
1Baylor Heart and Vascular Institute, Dallas, TX 75226, USA
2Baylor University Medical Center, Dallas, TX 75226, USA
3Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX 75226, USA
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There is emerging evidence to suggest that vitamin D deficiency is associated with adverse outcomes in COVID-19 patients. Conversely, vitamin D supplementation protects against an initial alveolar diffuse damage of COVID-19 becoming progressively worse. The mechanisms by which vitamin D deficiency exacerbates COVID-19 pneumonia remain poorly understood. In this review we describe the rationale of the putative role of endothelial dysfunction in this event. Herein, we will briefly review (1) anti-inflammatory and anti-thrombotic effects of vitamin D, (2) vitamin D receptor and vitamin D receptor ligand, (3) protective role of vitamin D against endothelial dysfunction, (4) risk of vitamin D deficiency, (5) vitamin D deficiency in association with endothelial dysfunction, (6) the characteristics of vitamin D relevant to COVID-19, (7) the role of vitamin D on innate and adaptive response, (8) biomarkers of endothelial cell activation contributing to cytokine storm, and (9) the bidirectional relationship between inflammation and homeostasis. Finally, we hypothesize that endothelial dysfunction relevant to vitamin D deficiency results from decreased binding of the vitamin D receptor with its ligand on the vascular endothelium and that it may be immune-mediated via increased interferon 1 α. A possible sequence of events may be described as (1) angiotensin II converting enzyme-related initial endothelial injury followed by vitamin D receptor-related endothelial dysfunction, (2) endothelial lesions deteriorating to endothelialitis, coagulopathy and thrombosis, and (3) vascular damage exacerbating pulmonary pathology and making patients with vitamin D deficiency vulnerable to death.

Key words:  Coagulation      COVID-19      cytokines      endothelial activation      endothelial dysfunction      inflammation      SARS-CoV-2      vitamin D      von Willebrand factor     
Submitted:  09 July 2020      Revised:  20 August 2020      Accepted:  08 September 2020      Published:  30 September 2020     
Fund: Baylor Health Care System Foundation
*Corresponding Author(s):  Jun Zhang     E-mail:

Cite this article: 

Jun Zhang, Peter A. McCullough, Kristen M. Tecson. Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19. Reviews in Cardiovascular Medicine, 2020, 21(3): 339-344.

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Fig. 1.  Schematic diagram showing a hypothesis of endothelial dysfunction in COVID-19 patients with vitamin D deficiency. A possible sequence of events may be described as (1) ACE2- related initial endothelial injury followed by VDR-related endothelial dysfunction, (2) endothelial lesions deteriorate to endothelialitis, coagulopathy, and thrombosis, and (3) vascular damage exacerbates pulmonary pathology and makes patients with vitamin D deficiency vulnerable to death. In the context of COVID-19 endothelialitis and coagulation, downstream pro-inflammatory mediators (E-selectin, ICAM-1, VCAM-1, JAM-1, and PECAM-1), cytokine and chemokines (IL-6 and IL-8) contribute to vascular inflammation, whereas downstream pro-coagulant mediators (P-selectin etc.) and pro-coagulant family (vWF, vWFpp, TF, PAI-1) contribute to coagulation. In the process of vasculopathy and coagulopathy, their initial lesions can be amplified by the bidirectional relationship between vascular inflammation and coagulation. ICAM-1= intercellular adhesion molecule-1, VCAM-1 = vascular cell adhesion molecule 1, JAM-1= junctional adhesion molecule-1, PECAM-1= platelet endothelial cell adhesion molecule-1, IL-6 and IL-8 = interleukin 6 and 8, vWF= von Willebrand factor, vWFpp, von Willebrand factor pro-peptide, TF= tissue factor, PAI-1= Plasminogen activating inhibitor-1.

[1] Ali, N. (2020) Role of vitamin D in preventing of COVID-19 infection, progression and severity. Journal of Infection and Public Health 20, S1876-0341(20)30531-1.
[2] Aranow, C. (2011) Vitamin D and the immune system. Journal of Investigative Medicine59, 881-886.
[3] Aygun, H. (2020) Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn-Schmiedeberg’s Archives of Pharmacology 393, 1157-1160.
[4] Biesalski, H. K. (2020) Vitamin D deficiency and co-morbidities in COVID-19 patients - A fatal relationship? NFS Journal 20, 10-21.
[5] Chen, H.-J., Tas, S. W. and de Winther, M. P. J. (2020) Type-I interferons in atherosclerosis. The Journal of Experimental Medicine 217, e20190459.
[6] Grant, W. B., Lahore, H., McDonnell, S. L., Baggerly, C. A., French, C. B., Aliano, J. L. and Bhattoa, H. P. (2020) Could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 12, 988.
[7] Greiller, C. L. and Martineau, A. R. (2015) Modulation of the immune response to respiratory viruses by vitamin D. Nutrients 7, 4240-4270.
[8] Hribar, C. A., Cobbold, P. H. and Church, F. C. (2020) Potential role of vitamin d in the elderly to resist COVID-19 and to slow progression of parkinson’s disease. Brain Sciences 10, 284.
[9] Ilie, P. C., Stefanescu, S. and Smith, L. (2020) The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research 32, 1195-1198.
[10] Jablonski, K. L., Chonchol, M., Pierce, G. L., Walker, A. E. and Seals, D. R. (2011) 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension 57, 63-69.
[11] Kanikarla-Marie, P. and Jain, S. K. (2016) 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). The Journal of Steroid Biochemistry and Molecular Biology 159, 94-101.
[12] Kundu, R., Theodoraki, A., Haas, C. T., Zhang, Y., Chain, B., Kriston-Vizi, J., Noursadeghi, M. and Khoo, B. (2017) Cell-type-specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes. Immunology 150, 55-63.
[13] Lee, P. Y., Li, Y., Richards, H. B., Chan, F. S., Zhuang, H., Narain, S., Butfiloski, E. J., Sobel, E. S., Reeves, W. H. and Segal, M. S. (2007) Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus. Arthritis and Rheumatism 56, 3759-3769.
[14] Mandal, M., Tripathy, R., Panda, A. K., Pattanaik, S. S., Dakua, S., Pradhan, A. K., Chakraborty, S., Ravindran, B. and Das, B. K. (2014) Vitamin D levels in Indian systemic lupus erythematosus patients: association with disease activity index and interferon alpha. Arthritis Research and Therapy 16, R49-R49.
[15] Margetic, S. (2012) Inflammation and hemostasis. Biochemia Medica 49-62.
[16] Martínez-Miguel, P., Valdivielso, J. M., Medrano-Andrés, D., Román-García, P., Cano-Peñalver, J. L., Rodríguez-Puyol, M., Rodríguez-Puyol, D. and López-Ongil, S. (2014) The active form of vitamin D, calcitriol, induces a complex dual upregulation of endothelin and nitric oxide in cultured endothelial cells. American Journal of Physiology-Endocrinology and Metabolism 307, E1085-E1096.
[17] Meltzer, D. O., Best, T. J., Zhang, H., Vokes, T., Arora, V. and Solway, J. (2020) Association of Vitamin D deficiency and treatment with COVID-19 incidence. medRxiv (In press).
[18] Mohammad, S., Mishra, A. and Ashraf, M. Z. (2019) Emerging role of Vitamin D and its associated molecules in pathways related to pathogenesis of thrombosis. Biomolecules 9, 649.
[19] Mousa, A., Naderpoor, N., Johnson, J., Sourris, K., de Courten, M. P. J., Wilson, K., Scragg, R., Plebanski, M. and de Courten, B. (2017) Effect of vitamin D supplementation on inflammation and nuclear factor kappa-B activity in overweight/obese adults: a randomized placebo-controlled trial. Scientific Reports 7, 15154-15154.
[20] Ngo, D. T., Sverdlov, A. L., McNeil, J. J. and Horowitz, J. D. (2010) Does vitamin D modulate asymmetric dimethylarginine and C-reactive protein concentrations? The American Journal of Medicine 123, 335-341.
[21] Peterson, C. A. and Heffernan, M. E. (2008) Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. Journal of inflammation (London, England) 5, 10-10.
[22] Pincombe, N. L., Pearson, M. J., Smart, N. A., King, N. and Dieberg, G. (2019) Effect of vitamin D supplementation on endothelial function - An updated systematic review with meta-analysis and meta-regression. Nutrition, Metabolism and Cardiovascular Diseases 29, 1261-1272.
[23] Prietl, B., Treiber, G., Pieber, T. R. and Amrein, K. (2013) Vitamin D and immune function. Nutrients 5, 2502-2521.
[24] Reynolds, J. A., Haque, S., Williamson, K., Ray, D. W., Alexander, M. Y. and Bruce, I. N. (2016) Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus. Scientific Reports 6, 22341-22341.
[25] Sassi, F., Tamone, C. and D’Amelio, P. (2018) Vitamin D: Nutrient, hormone, and immunomodulator. Nutrients 10, 1656.
[26] Stio, M., Martinesi, M., Bruni, S., Treves, C., Mathieu, C., Verstuyf, A., d’Albasio, G., Bagnoli, S. and Bonanomi, A. G. (2007) The Vitamin D analogue TX 527 blocks NF-κB activation in peripheral blood mononuclear cells of patients with Crohn’s disease. The Journal of Steroid Biochemistry and Molecular Biology 103, 51-60.
[27] Teixeira, T. M., da Costa, D. C., Resende, A. C., Soulage, C. O., Bezerra, F. F. and Daleprane, J. B. (2017) Activation of Nrf2-antioxidant signaling by 1,25-Dihydroxycholecalciferol prevents leptin-induced oxidative stress and inflammation in human endothelial Cells. The Journal of Nutrition 147, 506-513.
[28] Trochoutsou, A., Kloukina, V., Samitas, K. and Xanthou, G. (2015) Vitamin-D in the immune system: Genomic and non-genomic actions. Mini-Reviews in Medicinal Chemistry 15, 953-963.
[29] Uberti, F., Lattuada, D., Morsanuto, V., Nava, U., Bolis, G., Vacca, G., Squarzanti, D. F., Cisari, C. and Molinari, C. (2014) Vitamin D protects human endothelial cells from oxidative stress through the autophagic and survival pathways. The Journal of Clinical Endocrinology and Metabolism 99, 1367-1374.
[30] Virzì, G., Zhang, J., Nalesso, F., Ronco, C. and McCullough, P. (2018) The role of dendritic and endothelial cells in cardiorenal syndrome. Cardiorenal Medicine 8, 92-104.
[31] Weir, E. K., Thenappan, T., Bhargava, M. and Chen, Y. (2020) Does vitamin D deficiency increase the severity of COVID-19? Clinical Medicine 20, e107-e108.
[32] Wong, M. S. K., Delansorne, R., Man, R. Y. K. and Vanhoutte, P. M. (2008) Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat. American Journal of Physiology-Heart and Circulatory Physiology 295, H289-H296.
[33] Yancy, C. W. (2020) COVID-19 and African Americans. JAMA 323, 1891.
[34] Zemb, P., Bergman, P., Camargo, C. A., Cavalier, E., Cormier, C., Courbebaisse, M., Hollis, B., Joulia, F., Minisola, S., Pilz, S., Pludowski, P., Schmitt, F., Zdrenghea, M. and Souberbielle, J. (2020) Vitamin D deficiency and the COVID-19 pandemic. Journal of Global Antimicrobial Resistance 22, 133-134.
[35] Zhang, J., Bottiglieri, T. and McCullough, P. A. (2017) The central role of endothelial dysfunction in cardiorenal syndrome. Cardiorenal Medicine 7, 104-117.
[36] Zhang, J., DeFelice, A. F., Hanig, J. P. and Colatsky, T. (2010) Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury. Toxicologic Pathology 38, 856-871.
[37] Zhang, J., Hanig, J. P. and De Felice, A. F. (2012) Biomarkers of endothelial cell activation: Candidate markers for drug-induced vasculitis in patients or drug-induced vascular injury in animals. Vascular Pharmacology 56, 14-25.
[38] Zhang, Y., Leung, D. Y. M. and Goleva, E. (2014) Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma. Journal of Allergy and Clinical Immunology 133, 1744-1752.
[39] Zhang, Y., Leung, D. Y. M., Richers, B. N., Liu, Y., Remigio, L. K., Riches, D. W. and Goleva, E. (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. The Journal of Immunology 188, 2127-2135.
[40] Zhang, J., Tecson, K. T and McCullough, P. A. (2020) Endothelial dysfunction contributes to COVID-19 - associated vascular inflammation and coagulopathy. Reviews in Cardiovascular Medicine (in press).
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