PhD Scientific Days 2023

Translational Medicine I.

Vitamin D Deficiency Associated with Age-dependent Vascular Dysfunction in Mice

Text of the abstract

Introduction: Approximately 40% of the European population is vitamin D deficient. Several studies have demonstrated that vitamin D deficiency leads to a deterioration of the cardiovascular system, including vascular function, but the exact pathomechanism of the decline, especially in the elderly is unclear.
Aim: We aimed to investigate the vascular effects of vitamin D deficiency in young and aged mice and to identify the molecular and cellular mechanisms involved in the alteration of vascular reactivity.
Methods: Segments of the thoracic aorta isolated from wild-type (WT) and vitamin D receptor gene deficient (VDR KO) young and aged (3 and 11 months) male mice were examined under isometric conditions using myograph. Acetylcholine-induced endothelium-dependent relaxation was normalized to the pre-contraction induced by phenylephrine. We determined the mRNA levels of M3 muscarinic receptor (Chrm3), endothelial nitric oxide NO synthase (Nos3), soluble guanylate cyclase (Gucy1a1 and Gucy1b1) and macrophage marker (F4/80) genes from myographically studied vessel segments.
Results: While no differences were observed between contractions to phenylephrine, the relaxant effect of acetylcholine was significantly reduced in aortas of aged VDR KO mice compared to young WT, young KO and aged WT vessels. No significant differences were observed in the expression of Chrm3, Nos3, Gucy1a1 and Gucy1b1 genes between experimental groups, but older animals had higher levels of F4/80 mRNA regardless vitamin D status. There was a negative correlation between macrophage marker expression and the acetylcholine-induced relaxation (r=-0.2955, p<0.0106).
Conclusion: Our results suggest that vitamin D deficiency impairs endothelium-dependent relaxation of blood vessels in older age. This is not due to impaired NO production or smooth muscle signalling, but is probably due to reactive oxygen free radicals produced by macrophages in the vascular adventitia, which react with the NO produced, thereby reducing its dilator capacity. These findings suggest that older age induces a pro-inflammatory state with increased myeloid infiltration in the vascular wall, which is exacerbated by vitamin D deficiency and may increase the risk of developing cardiovascular disease.
Funding: ÚNKP-22-2-I-SE-26; ÚNKP-22-4-II-SE-17; TKP2021-EGA-25; PD-143327; NKFIH K-135683, K-139230