There is a negative correlation between blood 1,25(OH)2D3 concentrations and hypertension and cardiovascular diseases[21–24]. Vitamin D supplementation can decrease the blood pressure in a patient with hypertension[25]. The deficiency of 1,25(OH)2D3 may induce the cellular inflammatory response by activating RAS, and decrease vascular endothelial diastolic function and result in increased blood pressure[26–27]. Additionally, 1,25(OH)2D3 may reduce vascular resistance and decrease blood pressure by regulating smooth muscle cell and endothelial cell functions[28]. It has been indicated that 1,25(OH)2D3 has inhibitory effects on blood pressure and RAS. Using a 1α(OH)ase KO mice model, we demonstrate for the first time the effect of 1,25(OH)2D3 deficiency on brain VP secretion and cerebrovascular function.
The contribution of the CNS to the development and maintenance of high blood pressure is well established. Previously, we reported that endogenous 1,25(OH)2D3 deficiency may increase systemic and central oxidative stress, activating the systemic and central RAS and leading to higher blood pressure[10, 29]. Since lowering of blood pressure by the inhibition of the RAS system within systemic and central nervous system was documented by several studies[30–32], it seems that brain angiotensin II may play a key role in the contribution of CNS to hypertension. Angiotensin II has profound effects in the CNS via regulation of VP secretion[33]. Hypertension in mice with transgenic activation of the brain renin-angiotensin system is VP dependent. VP is required for the hypertension of mouse model induced by the brain RAS[34]. Injection of an antisense oligonucleotide of angiotensin in both PVN markedly decreased the blood plasma VP in the spontaneous hypertensive rat (SHR), and cerebral ventricular injection of angiotensin also increased PVN secretion of VP[35]. In this study, hypertension in the KO mice was accompanied by upregulated PVN and SON VP expression. Combined our previous study, we conclude that endogenous 1,25(OH)2D3 deficiency alter the central RAS and neuroendocrine hormone VP in mice.
Increased VP is recognized as a driver promoting the development and progression of hypertension in SHR and transgenic mouse[34, 36]. VP has a crucial role in regulating blood pressure through V1aR by stimulating vascular contractions, arterial baroreceptor reflex, sympathetic nerve activity, and water re-absorption, and blockade of the VP/V1aR signal results in decreased blood pressure[37]. Immunohistochemical studies have proven that, in rat hypothalamus, PVN and SON neuron vitamin D–binding proteins and VP coexist to an extent[38]. In this study, we examined effects of 1,25(OH)2D3 on the expression of VP in PVN and SON. Our results revealed that 1,25(OH)2D3 deficiency up-regulated the expression of VP in PVN and SON, whereas the administration of exogenous 1,25(OH)2D3 and NAC normalized VP expression in both PVN and SON. Our findings suggest 1,25(OH)2D3 downregulated hypothalamic magnocellular neuron VP secretion, subsequently producing an anti-hypertensive effect by regulating central oxidative stress.
The CBF and neuron activity communicating mechanism in the brain is termed a neurovascular unit[39]. Hypertension may cause pathological changes to the cerebral arteriola and arterioles, brain tissue hypoperfusion, and anoxia, damaging the nerve and blood vessel unit coupling activity and worsening brain functional injury. Untreated hypertension, poorly controlled hypertension, and high BP levels are associated with a decline in patients’ parenchymal CBF[40]. Wiesmann et al. reported that AngII-induced elevated systolic blood pressure results in impaired CBF and a decreased response to blood pressure lowering treatment in a mouse model for Alzheimer's disease[41–42]. As we known, endothelial dysfunction is associated with the oxidative stress in hypertension pathology[43–46]. Amounts of antioxidant scavengers, such as SOD, GPx, catalase and vitamin E, are decreased in patients with hypertension. The antioxidants NAC and tempol, completely normalized cerebrovascular reactivity in aged mice[47]. 1,25(OH)2D3 is a very effective antioxidant in systemic and central by upregulating the antioxidative defense systems[48–49]. Prophylactic vitamin D3 supplementation ameliorated neurobehavioral alterations, oxidative stress and neuroinflammation[50]. Administering 1,25(OH)2D3 to SHR greatly increased the mesenteric resistance arteriola contractility to VP[51], which shows that under hypertensive conditions, exogenous supplementation of active vitamin D can correct damaged vascular reactivity. Clinical investigation of the MR images of patients with cerebral ischemia revealed that decreased 25-hydroxyl vitamin D in the blood (≤ 25 nmol l− 1) is closely related with lacunar infarction, increased white matter signalling, and fine bleeding in the brain, indicating that the deficiency of active vitamin D is involved in brain vascular diseases[52]. In this experiment, we observed the cumulative vasoconstrictive and vasodilatory effect of ACh and the NOS inhibitor L-NNA, respectively, on the cerebrovascular system in mice, finding significantly decreased brain microvessel reactivity in the mice with 1,25(OH)2D3 deficiency, which was increased after diet correction with 1,25(OH)2D3 and NAC. We also found 1,25(OH)2D3 deficiency attenuates the evoked CBF in the 1α(OH)ase–/– mice compared with their WT littermates. These results indicate that 1,25(OH)2D3 protects cerebrovascular function, to a large extend, through an antioxidative effect.