Date Published: February 6, 2018
Publisher: Public Library of Science
Author(s): Éva Pál, Leila Hadjadj, Zoltán Fontányi, Anna Monori-Kiss, Zsuzsanna Mezei, Norbert Lippai, Attila Magyar, Andrea Heinzlmann, Gellért Karvaly, Emil Monos, György Nádasy, Zoltán Benyó, Szabolcs Várbíró, Alain-Pierre Gadeau.
Vitamin D deficiency (VDD) is a global health problem, which can lead to several pathophysiological consequences including cardiovascular diseases. Its impact on the cerebrovascular system is not well understood. The goal of the present work was to examine the effects of VDD on the morphological, biomechanical and functional properties of cerebral arterioles.
Four-week-old male Wistar rats (n = 11 per group) were either fed with vitamin D deficient diet or received conventional rat chow with per os vitamin D supplementation. Cardiovascular parameters and hormone levels (testosterone, androstenedione, progesterone and 25-hydroxyvitamin D) were measured during the study. After 8 weeks of treatment anterior cerebral artery segments were prepared and their morphological, biomechanical and functional properties were examined using pressure microangiometry. Resorcin-fuchsin and smooth muscle actin staining were used to detect elastic fiber density and smooth muscle cell counts in the vessel wall, respectively. Sections were immunostained for eNOS and COX-2 as well.
VDD markedly increased the wall thickness, the wall-to-lumen ratio and the wall cross-sectional area of arterioles as well as the number of smooth muscle cells in the tunica media. As a consequence, tangential wall stress was significantly lower in the VDD group. In addition, VDD increased the myogenic as well as the uridine 5’-triphosphate-induced tone and impaired bradykinin-induced relaxation. Decreased eNOS and increased COX-2 expression were also observed in the endothelium of VDD animals.
VDD causes inward hypertrophic remodeling due to vascular smooth muscle cell proliferation and enhances the vessel tone probably because of increased vasoconstrictor prostanoid levels in young adult rats. In addition, the decreased eNOS expression results in endothelial dysfunction. These morphological and functional alterations can potentially compromise the cerebral circulation and lead to cerebrovascular disorders in VDD.
Vitamin D deficiency (VDD) or insufficiency affects 1 billion people from all age groups worldwide. In addition to its well-characterized roles in calcium and phosphate homeostasis as well as in bone metabolism, 1,25-dihydroxyvitamin D—the active metabolite of vitamin D (VitD)—has numerous biological actions . Besides interacting with the intracellular VitD receptor and regulating the expression of up to 200 genes, it mediates non-genomic actions as well . VDD is associated with an increased risk of malignant tumor formation, autoimmune and infectious diseases as well as depression . Diabetes mellitus and metabolic syndrome are also linked to VDD, as 1,25-dihydroxyvitamin D improves β-cell function and insulin sensitivity . There is a growing body of evidence linking VDD to cardiovascular diseases including hypertension, atherosclerosis and coronary artery disease. Furthermore, a direct impact of VDD on endothelial dysfunction, arterial stiffness and vascular inflammation was also reported [2, 4, 5].
To our knowledge, the present study provides the first report of the deleterious changes in geometry and reactivity of cerebral arteries due to VDD. These alterations were associated with hypertrophic remodeling, increased myogenic tone, endothelial dysfunction, increased COX-2 and decreased eNOS expression. Interestingly, marked changes of morphology and reactivity developed in healthy young adult animals within a relatively short period (8 weeks) of VDD indicating the importance of normal VitD status for the maintenance of cerebrovascular functions.
The present study demonstrates the harmful effects of VDD on cerebral artery geometry and function in a rat model. We propose that VDD results in inward hypertrophic remodeling due to VSMC proliferation as well as in enhanced vessel tone due to increased vasoconstrictor prostanoid levels. In addition, impaired NO-mediated vasodilatation leads to endothelial dysfunction. Our results imply that a relatively short-term VDD in a relatively young age without any comorbidities can already induce marked morphological and functional alterations in the cerebral vasculature, which underlines the importance of sufficient VitD supply throughout the entire life in order to prevent stroke and other cerebrovascular diseases.