Vitamin D controls resistance artery function through regulation of perivascular adipose tissue hypoxia and inflammation

Abstract

Vitamin D deficiency in human subjects is associated with hypertension, metabolic syndrome and related risk factors of cardiovascular diseases. Serum 25-hydroxyvitamin D levels correlate inversely with adiposity in obese and lean individuals. Bioactive vitamin D, or calcitriol, exerts anti-inflammatory effects on adipocytes, preadipocytes and macrophages in vitro. We tested the hypothesis that vitamin D deficiency alters the phenotype of perivascular adipose tissue (PVAT) leading to impaired function in resistance artery. To examine the effects of vitamin D and PVAT on vascular reactivity, myograph experiments were performed on arteries, with or without intact PVAT, from mice maintained on vitamin D-deficient, vitamin D-sufficient or vitamin D-supplemented diet. Systolic blood pressure was significantly increased in mice on vitamin D-deficient diet. Importantly, vitamin D deficiency enhanced angiotensin II-induced vasoconstriction and impaired the normal ability of PVAT to suppress contractile responses of the underlying mesenteric resistance artery to angiotensin II and serotonin. Furthermore, vitamin D deficiency caused upregulation of the mRNA expression of tumor necrosis factor-α, hypoxia-inducible factor-1α and its downstream target lysyl oxidase in mesenteric PVAT. Incubation of mesenteric arteries under hypoxic conditions impaired the anti-contractile effects of intact PVAT on those arteries from mice on vitamin D-sufficient diet. Vitamin D supplementation protected arteries against hypoxia-induced impairment of PVAT function. The protective effects of vitamin D against vascular dysfunction, hypertension and cardiovascular diseases may be mediated, at least in part, through regulation of inflammatory and hypoxia signaling pathways in PVAT.

Role of Vitamin D in Cardiovascular Diseases

“…Perivascular adipose tissue (PVAT) in obesity produces factors that affect atherogenesis and smooth muscle cell proliferation, thereby affecting the contractile function. Pelham et al [98] demonstrated an association between vitamin D deficiency, impaired normal ability of PVAT to suppress contractile responses of the underlying mesenteric resistance artery to angiotensin II and serotonin, and enhanced angiotensin II-induced vasoconstriction. Vitamin D deficiency was also associated with the increased expression of TNF-α and heat-induced factor-1 alpha (HIF-1α).…”

Serum Klotho, vitamin D, and homocysteine in combination predict the outcomes of Chinese patients with multiple system atrophy

“…Previous reports have shown that 25(OH)D is associated with inflammation and may involve in the pathogenesis of PD . Although both Klt and 25(OH)D are correlated with neuroinflammation and age‐related diseases, the association of Klt and 25(OH)D with MSA severity has not been systemically elucidated. Homocysteine (Hcy) is a key product at the intersection of cysteine and methionine and is associated with neuroinflammation and cognitive dysfunction .…”

“…Klt, 25(OH)D and Hcy are not only associated with inflammation and oxidative stress but also play important roles in the pathogenesis of various neurodegenerative diseases . To our knowledge, the independent and combined effects of Klt, 25(OH)D and Hcy have not been investigated in assessing MSA patients yet.…”

“…[17][18][19] Previous reports have shown that 25(OH)D is associated with inflammation and may involve in the pathogenesis of PD. [20][21][22][23] Although both Klt and 25(OH)D are correlated with neuroinflammation 14,15,24 and age-related diseases, 13,16,22,23 the association of Klt and 25(OH)D with MSA severity has not been systemically elucidated.…”

C1q/TNF‐related protein 9 improves the anti‐contractile effects of perivascular adipose tissue via the AMPK‐eNOS pathway in diet‐induced obese mice

“…Perivascular adipose tissue (PVAT) has been recently demonstrated to be a highly active endocrine organ, producing and releasing a variety of bioactive substances. [1][2][3] The most important role of PVAT is to reduce vasoconstrictive responses to noradrenaline or phenylephrine (PHE) by releasing various relaxation factors; this is called an anti-contractile property. 4 However, in obesity there are structural and functional changes in PVAT, which can result in vascular dysfunction by influencing endothelial and smooth muscle cells.…”