Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases

Abstract

Deficiency in vitamin D (VitD), a lipid-soluble vitamin and steroid hormone, affects approximately 24% to 40% of the population of the Western world. In addition to its well-documented effects on the musculoskeletal system, VitD also contributes importantly to the promotion and preservation of cardiovascular health via modulating the immune and inflammatory functions and regulating cell proliferation and migration, endothelial function, renin expression, and extracellular matrix homeostasis. This brief overview focuses on the cardiovascular and cerebrovascular effects of VitD and the cellular, molecular, and functional changes that occur in the circulatory system in VitD deficiency (VDD). It explores the links among VDD and adverse vascular remodeling, endothelial dysfunction, vascular inflammation, and increased risk for cardiovascular and cerebrovascular diseases. Improved understanding of the complex role of VDD in the pathogenesis of atherosclerotic cardiovascular diseases, stroke, and vascular cognitive impairment is crucial for all cardiologists, dietitians, and geriatricians, as VDD presents an easy target for intervention.

Keywords: VCI; aging; cerebral circulation; cerebrovascular disease; cholecalciferol; ergocalciferol; hypertension; stroke; vascular cognitive impairment; vitamin D; vitamin D2.

Figure 1

Genomic actions of vitamin D. 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) binds to the vitamin D receptor (VDR) and promotes its heterodimerization with the retinoid X receptor (RXR). The ligand-bound VDR/RXR complex binds to the vitamin D response elements (VDRE) in the promoters of numerous genes and modulates their transcription. Therefore, 1,25(OH)₂D₃ regulates several physiological processes, such as cell proliferation, differentiation, and inflammation [13]. Figure reproduced from “Vitamin D Deficiency and the Risk of Cerebrovascular Disease.” by Kim et al., Antioxidants (Basel), 2020, 9, 327, doi:10.3390/antiox9040327. The original figure was published (and can be reproduced) under the terms of CC-BY 4.0 [13].

Figure 2

Overview of the cardiovascular system-related impacts of vitamin D (TSP: thrombospondin, PAI-1: plasminogen activator inhibitor-1, RAS: renin-angiotensin system, T_H1: T helper type 1 cell, T_H2: T-helper type 2 cell; “See Figure 4” refers to Figure 4 of the original article by Norman PE and Powell JT [1]). Figure reproduced from “Vitamin D and cardiovascular disease” by Norman PE and Powell JT, Circ Res 2014, 114, 379–393, doi:10.1161/circresaha.113.301241. [1] with permission of the publisher. Copyright 2014, American Heart Association, Inc.

Figure 3

Representative actions of vitamin D deficiency in the (cerebro)vascular wall. Vitamin D deficiency impairs vascular functions via several pathways, including reductions in nitric oxide (NO) production, due to decreased endothelial nitric oxide synthase (eNOS) expression, phosphorylation, and dimerization. In addition, enhanced level of reactive oxygen species (ROS), resulting mainly from decreased expression of cytosolic copper-zinc superoxide dismutase (CuZn-SOD) and upregulation of the free radical generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme and its subunits in endothelial cells, contributes to endothelial dysfunction. Furthermore, vitamin D deficiency is associated with increased production of pro-inflammatory mediators, for instance, tumor necrosis factor-α (TNF-α) and cyclooxygenase 2 (COX-2), leading to vascular inflammation. Remodeling of extracellular matrix (ECM) and increased collagen–elastin ratio of vessel wall—particularly due to altered expression and activity of specific matrix metalloproteinases (MMPs)—as well as changes in vascular smooth muscle cell (VSMC) proliferation, may result in vascular remodeling and stiffening.