Elimination of Vitamin D Receptor in Vascular Endothelial Cells Alters Vascular Function

Ni, Wei; Watts, Stephanie W.; Ng, Michael; Chen, Songcang; Glenn, Denis J.; Gardner, David G.

doi:10.1161/hypertensionaha.114.03971

Cited by 141 publications

(114 citation statements)

References 56 publications

(76 reference statements)

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“…Mechanistically, the lack of Vdr signaling results in chronically lower bioavailability of the vasodilator nitric oxide (NO) due to reduced expression of NO synthesizing enzyme, and these effects are independent of changes in the renin-angiotensin system (19). In accordance herewith, deletion of the Vdr specifically in endothelial cells results in endothelial dysfunction evidenced by impaired blood vessel relaxation, an effect that was associated with reduced endothelial NO synthase expression (329). Moreover, mice with cardiomyocyte-selective deletion of Vdr also develop cardiac hypertrophy, independent of changes in the renin-angiotensin system and thus indicating a direct in vivo antihypertrophic effect of 1,25(OH) 2 D 3 (78).…”

Section: Mechanisms: In Vitro Data and Mouse Datamentioning

confidence: 65%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,435

1,234

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, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Section: Mechanisms: In Vitro Data and Mouse Datamentioning

confidence: 65%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,435

1,234

View full text Add to dashboard Cite

show abstract

“…Vitamin D supplementation has been shown to improve human insulin resistance among patients with glucose intolerance [92,93]. Furthermore, our endothelium-specific VDR knockout mice impaired endothelium-dependent vascular relaxing function, which also contributes to BP elevation [63]. Although further research needs to elucidate the mechanisms by which vitamin D supplementation improves glucose metabolism in type 2 diabetes patients, subsequently lowers BP, the promising preliminary data from these trials are interesting.…”

Section: Effect Of Vitamin D Administration On Bp In Vitamin D-deficimentioning

confidence: 96%

“…BP is regulated by the heart, kidney, vasculature, and sympathetic-CD4+ Tcell system, all of which express VDR. We have made cardiomyocytespecific VDR-/-mice [57], endothelium-specific VDR-null mice [63], and renal collecting duct-specific VDR-/-mice (Chen et al, unpublished data) using aquaporin-2-Cre mice [64], all of which demonstrate normal BP. Increasing evidence has shown that deletion of a single gene in VSMCs can be sufficient to develop HTN [65][66][67][68].…”

Section: Vitamin D Signaling Defect In Vsmcs and Cd+ T Cells Seems Prmentioning

confidence: 99%

Effect of Vitamin D on the Treatment and Prevention of Essential Hypertension

Chen¹

2017

Drug Des

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The vast majority of epidemiological studies have consistently shown that vitamin D levels are inversely related to blood pressure (BP) and the incidence of hypertension (HTN). Animal studies from diet-induced or genetic models of vitamin D deficiency suggest that vitamin D deficiency directly causes HTN. Based on basic and clinical studies, modestly increased renin expression in genetic mouse models of vitamin D deficiency is associated with, but not causally linked to vitamin D deficiency-induced HTN. Our mechanistic studies indicate that overexpression of a novel target gene seems to play a critical role in vitamin D-deficient HTN, and that vitamin D signaling defect in vascular smooth muscle cells and CD4+ T lymphocytes seems predominantly be responsible for vitamin D deficiencymediated HTN. The data from many clinical trials have consistently demonstrated a minimal or no effect of shortterm vitamin D supplementation on BP in normotensive healthy individuals, but long-term vitamin D supplementation should prevent the development of essential HTN (EH) at high-risk susceptible people. More than 13 randomized controlled trials have shown that vitamin D repletion significantly reduces BP in vitamin D-deficient EH patients, which appears to be more effective in those with type 2 diabetes or impaired glucose tolerance. Short-term administration of active vitamin D or its analogue has a better antihypertensive role than natural vitamin D in the treatment of vitamin D-deficient EH. While these promising data from relatively small trials have displayed potential beneficial vitamin D effect on EH, it is urgently needed to comprehensively elucidate molecular mechanisms of vitamin D deficiency-induced HTN, which will provide a solid theoretical basis to well design large randomized controlled trials to further address the antihypertensive role of vitamin D in vitamin D-deficient EH patients. Currently, EH is lacking an etiology-specific therapy. Identification of vitamin D deficiency as an environmental stressor that triggers the development of EH at vulnerable individuals will make a great advance in the field of EH research.Keywords: Vitamin D; Deficiency; Blood pressure; Essential hypertension; Molecular mechanisms; Clinical trials Etiology-Specific Treatment for EH is a Knowledge GapMore than 95% hypertensive patients suffer from EH, a chronic disease that displays an elevated BP phenotype with unknown etiology. EH can lead to stroke, coronary artery disease, peripheral artery disease, heart failure, renal failure and increased mortality if it is not well controlled [1]. Although there are several classes of antihypertensive medications available, in America, 50% of hypertensive patients do not have their BP well-controlled and about 5 million patients are resistant to antihypertensive treatment with a combination of at least three antihypertensive medications [2]. One of critical problems is lacking an etiology-specific effective therapy for EH. Currently, treatment of EH is largely empiric, and the lesseff...

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“…However, it is unclear whether ELD affected the function of adipose tissue such as the capacity for adipocytokine production. Although endothelial VDR is important for endothelial function (Ni et al 2014), it is not yet known which mechanism is more important in endothelial protection in OVX rats, endothelial VDR activation, or adipocytokine production. There are many reports demonstrated that vitamin D 3 is beneficial for endothelial function.…”

Section: Limitations Of This Studymentioning

confidence: 99%

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats

Serizawa¹,

Tashiro²,

Takeda

et al. 2015

Journal of Endocrinology

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Postmenopausal women have high incidence of cardiovascular events as estrogen deficiency can cause endothelial dysfunction. Vitamin D is reported to be beneficial on endothelial function, but it remains controversial whether vitamin D is effective for endothelial dysfunction under the treatment for osteoporosis in postmenopausal women. The aim of this study was to evaluate the endothelial protective effect of eldecalcitol (ELD) in ovariectomized (OVX) rats. ELD (20 ng/kg) was orally administrated five times a week for 4 weeks from 1 day after surgery. After that, flow-mediated dilation (FMD) as an indicator of endothelial function was measured by high-resolution ultrasound in the femoral artery of living rats. ELD ameliorated the reduction of FMD in OVX rats. ELD inhibited the increase in NOX4, nitrotyrosine, and p65 and the decrease in dimer/monomer ratio of nitric oxide synthase in OVX rat femoral arteries. ELD also prevented the decrease in peroxisome proliferator-activated receptor gamma (PPARg) in femoral arteries and cultured endothelial cells. Although PPARg is known to inhibit osteoblastogenesis, ELD understandably increased bone mineral density of OVX rats without increase in PPARg in bone marrow. These results suggest that ELD prevented the deterioration of endothelial function under condition of preventing bone loss in OVX rats. This endothelial protective effect of ELD might be exerted through improvement of endothelial nitric oxide synthase uncoupling, which is mediated by an antioxidative effect through normalization of vascular PPARg/NF-kB signaling.

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Elimination of Vitamin D Receptor in Vascular Endothelial Cells Alters Vascular Function

Cited by 141 publications

References 56 publications

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Effect of Vitamin D on the Treatment and Prevention of Essential Hypertension

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats

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