Aim: We aimed to examine the alterations of the insulin signaling pathway, autophagy, nitrative stress and the effect of vitamin D supplementation in the liver and ovaries of vitamin D deficient hyperandrogenic rats. Methods: Female Wistar rats received eight weeks of transdermal testosterone treatment and lived on a low vitamin D diet (D–T+). Vitamin D supplementation was achieved by oral administration of vitamin D3 (D+T+). Sham-treated (D+T–) and vitamin D deficient animals (D–T–) served as controls. (N = 10–12 per group). Results: D–T+ animals showed decreased LC3 II levels in the liver and increased p-Akt/Akt and p-eNOS/eNOS ratios with decreased insulin receptor staining in the ovaries. Vitamin D supplementation prevented the increase of Akt phosphorylation in the ovaries. Vitamin D deficiency itself also led to decreased LC3 II levels in the liver and decreased insulin receptor staining in the ovaries. D–T+ group showed no increase in nitrotyrosine staining; however, the ovaries of D–T– rats and the liver of D+T+ animals showed increased staining intensity. Conclusion: Vitamin D deficiency itself might lead to disrupted ovarian maturation and autophagy malfunction in the liver. Preventing Akt phosphorylation may contribute to the beneficial effect of vitamin D treatment on ovarian function in hyperandrogenism.
Polycystic ovary syndrome (PCOS) is associated with elevated cardiovascular risk. Early vascular dysfunction may lead to the development of cardiovascular disease in PCOS. Vitamin D deficiency (VDD) is a common comorbidity of PCOS that contributes to the pathogenesis of the disease and its complications. Both PCOS and VDD are accompanied by increased oxidative stress that may be involved in the arising vascular dysfunction. We aimed to investigate the role of vitamin D status on aortic function. PCOS was induced by an 8-week-long transdermal testosterone treatment of female rats, and low and adequate vitamin D status was achieved by dietary means. Contraction and relaxation abilities of isolated aortic segments were measured by myograph. Resorcin-fuchsin staining and immunohistochemical labeling of 3-nitrotyrosine were performed. No difference was shown in the norepinephrine-induced contraction of the aortas of different groups, whereas we detected reduced acetylcholine- and insulin-evoked relaxation in VDD groups. A lower level of resorcin-fuchsin staining and elevated 3-nitrotyrosine immunostaining was observed in VDD. In our study, we demonstrated early endothelial dysfunction in VDD PCOS rat model. Vitamin D supplementation could prevent vascular disturbances, while VDD itself damaged endothelium-dependent vasorelaxation and induced nitrative stress.
We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D- animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.
In polycystic ovary syndrome (PCOS) hyperandrogenism and metabolic dysfunction increase cardiovascular risk. Vitamin D3 deficiency is a common comorbidity in PCOS. Our aim was to examine the alterations of insulin-induced vasodilation and receptor expression in rat aorta in a PCOS model. Methods: Female Wistar rats were treated as follows: 1. vitamin D supplemented group (D+T−); 2. vitamin D deficient (D−T−), 3. vitamin D supplemented with transdermal testosterone application (D+T+) and 4. vitamin D deficient with transdermal testosterone (D−T+). Wire myograph was used for testing insulin relaxation of aorta rings in physiological salt solution and under NOS inhibition. Insulin (IR) and vitamin D receptor (VDR) density was examined by immunohistochemistry. Results: Insulin-induced vasodilatation of the aorta rings were significantly lower in both vitamin deficient compared to the vitamin supplemented groups (p < 0.05). NOS inhibition significantly reduce the relaxation. Aorta endothelial IR expression was significantly higher in the vitamin D deficient group, meanwhile in the testosterone-treated groups (D+T+; D−T+) the expression was significantly lower (Area%: D+: 0.830 ± 0.10; D+T+: 0.298 ± 0.06; D−: 1.364 ± 0.12; D−T+: 0.354 ± 0.15, p < 0.05 in D− & D+T+ & D−T+ vs D+. p < 0.01 D+T+ & D−T+ vs D−). VDR density was significantly higher in the vitamin D deficient groups in comparison to the supplemented groups (Area% VDR: D+: 41.56 ± 5.58 vs D−: 60.63 ± 5.23) Testosterone treatment have not any effect on VDR expression. Conclusion: Vitamin-D deficiency causes impaired insulin induced vasodilation. Increased IR density could not compensate altered insulin-induced relaxation.
Objective:Polycystic ovary syndrome (PCOS) and vitamin D deficiency are associated with elevated cardiovascular risk, whereas vitamin D deficiency is a common comorbidity in PCOS that may contribute to the pathogenesis and complications of the disease. Our aim was to investigate the role of vitamin D status on the aortic function of hyperandrogenic female rats showing the symptoms of PCOS.Design and method:Female Wistar rats received an 8-week-long transdermal Androgel treatment to induce hyperandrogenism, another group remained untreated. Half of each group was fed with vitamin D reduced rat chow, while the other half received normal chow with further supplementation of vitamin D. Norepinephrine-induced contraction, acetylcholine, insulin, and estrogen-induced relaxation of thoracic aortae was examined by wire myography. Elastic fiber density was evaluated on resorcin-fuchsin stained tissue sections. Estrogen receptor alpha, endothelial nitric oxide synthase (eNOS), and cyclooxygenase 2 (COX-2) density and protein tyrosine nitration (NT) was measured by immunohistochemistry.Results:There was no difference in the norepinephrine-induced contraction of the aortas between experimental groups. Reduced acetylcholine-, insulin- and estrogen-evoked relaxation was observed in vitamin D deficient groups. A lower level of resorcin-fuchsin staining and elevated 3- nitrotyrosine immunostaining was observed in non-hyperandrogenic vitamin D deficient rats. eNOS staining intensity was reduced by vitamin D deficiency, while COX-2 density was increased by testosterone treatment. Estrogen receptor alpha density was increased by testosterone treatment but reduced by vitamin D deficiency.Conclusions:We demonstrated an early endothelial dysfunction in a rat model of vitamin D deficient polycystic ovary syndrome. Vitamin D supplementation could prevent vascular damage. On the other hand, vitamin D deficiency itself led to decreased endothelium-dependent relaxation and increased nitrative stress. Vitamin D deficiency also led to decreased estrogen receptor alpha and eNOS density independently from hyperandrogenism. Vitamin D deficiency found in approximately 80% of PCOS women may have a significant role in the development of vascular dysfunction and may contribute to their increased cardiovascular risk.
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