Introduction: Approximately 40% of the European population is vitamin D deficient,
and the prevalence increases with age. In recent years, several studies have demonstrated
that vitamin D deficiency leads to a deterioration of the cardiovascular system, including
vascular function, but the precise pathomechanism of this decline, particularly in
the elderly,
is not fully understood.
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. The vascular responses to
phenylephrine were normalized to 124 mM K+
-induced contraction, and acetylcholineinduced endothelium-dependent relaxation was
normalized to the pre-contraction induced
by phenylephrine. In addition, we determined the expression levels of relaxation-associated
M3 muscarinic receptor (Chrm3), endothelial nitric oxide NO synthase (Nos3), soluble
guanylate cyclase (Gucy1a1 and Gucy1b1) and adventitial macrophage marker (F4/80)
genes
from myographically studied vessel segments. The presence of the macrophages was
examined using immunhistochemistry.
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 (with 27.5; 25.7 and 25.7 %). No
significant differences were observed in the expression of Chrm3, Nos3, Gucy1a1 and
Gucy1b1
genes between experimental groups, but VDR deficient animals had higher levels of
F4/80
mRNA regardless of age. There was a negative correlation between the expression of
macrophage marker and the relaxation induced by acetylcholine (r=-0.2955, p<0.0106).
Conclusion: Our results suggest that vitamin D deficiency impairs endotheliumdependent
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 vitamin D deficiency induces a proinflammatory
state with increased myeloid infiltration in the vascular wall, which is
exacerbated with age. The resulting endothelial dysfunction may increase the risk
of
developing cardiovascular disease.
