Abstract
Hyperandrogenism is a risk factor of cerebrovascular diseases as androgens can alter markedly the regulation of cerebrovascular tone. We examined the combined impact of androgen excess and vitamin D deficiency (VDD), a common co-morbidity in hyperandrogenic disorders, on remodeling and testosterone-induced vascular responses of anterior cerebral arteries (ACA) in order to evaluate the interplay between androgens and VDD in the cerebral vasculature. Male and female Wistar rats were either fed with vitamin D deficient or vitamin D supplemented diet. Half of the female animals from both groups received transdermal testosterone treatment. After 8 weeks, vessel lumen, wall thickness and testosterone-induced vascular tone of isolated ACA were determined using pressure microangiometry and histological examination. Androgen receptor protein expression in the wall of cerebral arteries was examined using immunohistochemistry. In female rats only combined VDD and testosterone treatment decreased the lumen and increased the wall thickness of ACA. In males, however VDD by itself was able to decrease the lumen and increase the wall thickness. Vascular reactivity showed similar alterations: in females, testosterone constricted the ACA only after combined VDD and hyperandrogenism, whereas in males VDD resulted in increased testosterone-induced contractions in spite of decreased androgen receptor expression. In conclusion, a marked interplay between hyperandrogenism and VDD results in inward remodeling and enhanced testosterone-induced constrictions of cerebral arteries, which might compromise the cerebral circulation and thus, increase the risk of stroke in the long term. In addition, the early cerebrovascular manifestation of VDD appears to require androgen excess and thus, depends on gender.
Highlights
Sex steroids have considerable impact on the cerebral circulation [1] since endogenous and exogenously administered gonadal hormones influence the cerebrovascular tone and blood perfusion under physiological and pathophysiological conditions [2]
Representative images of the anterior cerebral artery showing the testosterone induced vasoconstriction in female rats subjected to combined vitamin D deficiency (VDD) and androgen excess. (C) Anterior cerebral artery segment under physiological conditions. (D) Anterior cerebral artery segment after the application of 10−6 mol/L testosterone
In the present study both physiological (10−9 mol/L) and supraphysiological concentrations (10−8–10−6 mol/L) of testosterone [18] induced vasoconstrictions in females. These results indicate that, in addition to vascular remodeling, the testosterone-induced tone caused by VDD and hyperandrogenism might lead to cerebrovascular disorders, as sex steroids may contribute markedly to the maintenance of cerebrovascular tone and reactivity [2]. Both hyperandrogenism and VDD are associated reportedly with cerebrovascular disorders [14, 15]; the present study shows that they synergistically cause deleterious alterations in the morphology and reactivity of anterior cerebral arteries (ACA) within a relatively short time, which could facilitate the development of cerebrovascular diseases or aggravate their outcomes
Summary
Sex steroids have considerable impact on the cerebral circulation [1] since endogenous and exogenously administered gonadal hormones influence the cerebrovascular tone and blood perfusion under physiological and pathophysiological conditions [2]. The impact of estradiol on the cerebral circulation is well known, the effect of testosterone on cerebral vessels is more obscure [1, 2]. Effectiveness of vitamin D (VitD) supplementation in the prevention of cardiovascular events is obscure [4], vitamin D deficiency (VDD) appears to be linked to the metabolic syndrome as well as to cardiovascular diseases including hypertension, atherosclerosis and cerebrovascular disturbances in both genders [5, 6]. The role of VitD in the modulation of arterial function has already been described in several vessel types [8,9,10]; for instance, both animal [7] and human studies [11] imply the presence of cerebrovascular impairment in VDD
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