Active vitamin D corrects cerebrovascular dysfunction and aberrant vasopressin expression in the hypertension phenotype of 1α-hydroxylase knockout mice

Abstract Background Under hypertensive conditions, vitamin D has a protective effect on the brain. Our previous research showed that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] negatively regulates hypertension and central renin–angiotensin system activation partly through a central antioxidative mechanism in 1α-hydroxylase knockout [1α(OH)ase–/–] mice. To further confirm whether the endogenous 1,25(OH)2D3 deficiency and exogenous 1,25(OH)2D3 supplementation alter cerebrovascular function and vasopressin expression through antioxidation, we provided 1α(OH)ase–/– mice and their wild-type littermates with normal diet; a high-calcium, high-phosphorus rescue diet with N-acetyl-l-cysteine supplementation; or 1,25(OH)2D3 subcutaneous injection. We analysed and compared the changes in arterial blood pressure, brain microvessel reactivity, cerebral blood flow, expression of hypothalamic vasopressin, and brain/blood oxidation and antioxidative indices using caudal artery plethysmography, isolated microvessel pressure myographs, laser Doppler flowmetry, immunohistochemistry, western blot and biochemistry. Results Compared with their wild-type littermates, the hypertension phenotype was present in the 1α(OH)ase–/– mice, hypothalamic paraventricular nucleus and supraoptic nucleus vasopressin expression was significantly upregulated, and the posterior cerebral artery reaction to the vasodilatory effect of acetylcholine and vasoconstrictive effect of the nitric oxide synthase inhibitor L-nitro-arginine was significantly decreased. Brain/blood oxidative stress was increased, but the antioxidative parameters were decreased. These pathologic changes were corrected by 1,25(OH)2D3 or N-acetyl-l-cysteine plus rescue diet. Conclusions our findings indicate that 1,25(OH)2D3 has an inhibitory effect on vasopressin expression and cerebrovascular dysfunction. 1,25(OH)2D3 may be a promising protective intervention to reduce brain impaired induced by oxidative stress in the hypertension phenotype of 1α(OH)ase–/– mice.