Circadian melatonin suppression and vitamin D deficiency disrupt aortic reactivity via MT1/MT2 and VDR-dependent mechanisms in rats.

Circadian disruption and vitamin D deficiency (VDD) are increasingly prevalent and independently associated with cardiovascular dysfunction. However, their combined impact on vascular reactivity and receptor signaling remains insufficiently defined. This study investigated the independent and interactive effects of melatonin (MEL) suppression induced by continuous light (CL) or pinealectomy (Px) and VDD on vascular contractility, endothelial function, and MT1/vitamin D receptor (VDR) gene expression in rat thoracic aorta. Isolated aortic rings were subjected to cumulative concentration response curves for phenylephrine (PE) and acetylcholine (ACh). Pharmacodynamic parameters, potency (pD₂), maximal efficacy (Emax), and area under the curve (AUC) were calculated. MEL and calcitriol modulation with receptor antagonism was performed to determine receptor dependence. Relative MT1 and VDR mRNA expression was quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). CL, Px, and VDD significantly enhanced PE-induced maximal contraction, with the combined deficiency groups exhibiting the greatest augmentation of α₁-adrenergic responsiveness. In contrast, ACh-induced relaxation was selectively impaired under dual-deficiency conditions, characterized by reduced Emax without major changes in pD2, indicating compromised endothelial efficacy rather than altered receptor sensitivity. MEL attenuated vasoconstriction and enhanced relaxation in a receptor-dependent manner, whereas calcitriol potentiated contractility through VDR signaling. Notably, combined CL + VDD produced marked upregulation of MT1 (~ 10-fold) and VDR (~ 108-fold), suggesting compensatory transcriptional remodeling. Circadian disruption and VDD synergistically promote vascular hyperreactivity and endothelial dysfunction. Their convergence amplifies α₁-adrenergic signaling while impairing nitric oxide (NO) mediated relaxation, identifying a mechanistic axis linking modern light exposure and hypovitaminosis D to heightened cardiovascular risk.