RESUMO
BACKGROUND: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of male rats in cases of different vitamin D supply. METHODS: Four-week-old male Wistar rats were divided into a control group (n = 11) with optimal vitamin D supply (300 IU/kgbw/day) and a VDD group (n = 11, <0.5 IU/kgbw/day). After 8 weeks of treatment, intramural coronary artery segments were microprepared, their pharmacological reactivity was examined by in vitro microangiometry, and their receptor expression was investigated by immunohistochemistry. RESULTS: Thromboxane A2 (TXA2)-agonist induced reduced vasoconstriction, testosterone (T) and 17-ß-estradiol (E2) relaxations were significantly decreased, a significant decrease in thromboxane receptor (TP) expression was shown, and the reduction in estrogen receptor-α (ERα) expression was on the border of significance in the VDD group. CONCLUSIONS: VD-deficient male coronary arteries showed deteriorated pharmacological reactivity to TXA2 and sexual steroids (E2, T). Insufficient vasoconstrictor capacity was accompanied by decreased TP receptor expression, and vasodilator impairments were mainly functional. The decrease in vasoconstrictor and vasodilator responses results in narrowed adaptational range of coronaries, causing inadequate coronary perfusion that might contribute to the increased CV risk in VDD.
Assuntos
Arteríolas/patologia , Doença da Artéria Coronariana/patologia , Estradiol/farmacologia , Testosterona/farmacologia , Tromboxano A2/farmacologia , Deficiência de Vitamina D/complicações , Androgênios/farmacologia , Animais , Arteríolas/metabolismo , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Modelos Animais de Doenças , Estrogênios/farmacologia , Masculino , Ratos , Ratos Wistar , Receptores de Tromboxanos/metabolismo , Vasoconstrição , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/patologiaRESUMO
The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk.
Assuntos
Artérias Carótidas/fisiopatologia , Caracteres Sexuais , Vasoconstrição , Vasodilatação , Deficiência de Vitamina D/fisiopatologia , Animais , Artérias Carótidas/metabolismo , Feminino , Masculino , Ratos , Ratos Wistar , Deficiência de Vitamina D/metabolismoRESUMO
Vitamin D (VitD) hypovitaminosis and androgen excess (AE) are both risk factors for cardiovascular diseases in fertile women. However, the possible early interaction between AE and VitD status is not clear. Our goal was to describe how VitD status influences early changes in the biomechanical reactivity of small coronary arterioles in adult female rats after transdermal testosterone treatment. Forty-six adolescent, 90-110-gram-weighed female Wistar rats were randomly grouped into 4 groups. Twenty-four animals received an optimal VitD-supplemented diet, from which 12 animals underwent transdermal testosterone treatment. Twenty-two animals received a VitD-deficient diet, from which 11 were treated with testosterone. At 8â¯weeks of treatment, invasive arterial blood pressure was registered after in vivo cannulation of carotid artery. Arteriolar end and side branches (200⯵m diameter) of the left anterior descendent coronary artery (LAD) were obtained and examined with pressure arteriography in vitro. Similar segments were removed for histological examination. The inner and outer radii of the arterioles were measured using video-microscopy. Normal myogenic tone, maximal passive vasorelaxation and vasoconstriction of the arterioles were measured and statistically analyzed. The vessels' maximal smooth muscle relaxant potential, thromboxane-induced contraction capacity and normal myogenic tone were significantly influenced by actual VitD status. A lower relaxation capacity and increased wall thickness were observed in VitD-deficient groups, which could cause rigidity of the coronary arterioles and elevate cardiovascular risk. Supplementation of VitD could improve myogenic tone and relaxation and hold cardiovascular benefits.
Assuntos
Arteríolas/fisiopatologia , Vasos Coronários/fisiopatologia , Tecido Elástico/fisiopatologia , Hiperandrogenismo/fisiopatologia , Vasoconstrição , Vasodilatação , Deficiência de Vitamina D/fisiopatologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/patologia , Fenômenos Biomecânicos , Colecalciferol/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Modelos Animais de Doenças , Módulo de Elasticidade , Tecido Elástico/efeitos dos fármacos , Tecido Elástico/patologia , Feminino , Hiperandrogenismo/patologia , Ratos Wistar , Remodelação Vascular , Rigidez Vascular , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/patologiaRESUMO
Vitamin D (vitD) insufficiency affects 1 billion people worldwide. Androgen excess (AE) occurs in 8% of fertile females. There are few data about the combined effect of vitD deficiency and AE on the early biomechanical changes of cerebral arterioles in fertile-aged female. Forty-six adolescent female Wistar rats (21-28 day-old, weighing 90-110 g) were grouped randomly in four groups: vitD supplemented groups with and without transdermal testosterone (T) treatment, as well as vitD deficient groups also with and without transdermal T (n = 11 or 12, in all cases). After 8 weeks of treatment, anterior cerebral arterioles (in vivo diameter of 90-130 µm) were obtained and cylindrical segments were examined by pressure arteriography. Myogenic tone, tangential stress and incremental elastic moduli were computed and statistically analyzed. Elastic density was studied on resorcin-fuchsin-stained histological section. VitD deficiency with T treatment resulted in significantly lower inner radii and higher wall thickness values with reduced tangential stress and increased elastic fiber density. VitD deficiency reduced myogenic tone at higher intraluminar pressures (>110 mmHg). Our conclusion is that plasma vitD level is an important factor in the control of myogenic tone in cerebral resistance arteries. AE and vitD deficiency acting parallel induce remodeling of their wall.
Assuntos
Androgênios/farmacologia , Arteríolas/fisiopatologia , Colecalciferol/farmacologia , Testosterona/farmacologia , Remodelação Vascular/fisiologia , Deficiência de Vitamina D/fisiopatologia , Angiografia , Animais , Arteríolas/efeitos dos fármacos , Feminino , Ratos , Ratos Wistar , Remodelação Vascular/efeitos dos fármacosRESUMO
The aim of our study was to identify whether vitamin-D deficiency (VDD) can alter the geometry of the coronary-resistance-artery system. Male Wistar rats were divided into vitamin-D-deficient (VD-, n = 10) and vitamin-D-supplemented (VD+, n = 8) groups. After eight weeks, branches and segments of the left-anterior-descending-coronary-artery (LAD) network were analyzed by a video-microscopy technique. Segments were divided into 50 µm-long cylindrical ring units. VDD did not increase the number of morphological abnormalities. The number of segments did not differ between the groups (VD-: 210 and VD+: 224; pooled data of 8 networks). A larger lumen area of branches was found in VD+ group, while 1-4-order branches were lengthier in the VD- group. VD- rats had less rich coronary-resistance-artery networks in terms of 50 µm-long units. (VD-: 6365 vs. VD+: 6602; pooled data of 8 networks). VD+ animals were richer in the 100-350 µm outer diameter range, and VD- animals were richer in the 400-550 µm-diameter units. In VD- rats, 150-200 and 300 µm units were almost missing at higher flow distances from the orifice. Serum vitamin-D alterations caused by dietary changes can affect the geometry of the coronary-artery network, which may contribute to vitamin-D-dependent changes in cardiovascular mortality.
Assuntos
Vasos Coronários , Deficiência de Vitamina D , Animais , Suplementos Nutricionais , Masculino , Ratos , Ratos Wistar , Roedores , Vitaminas/farmacologiaRESUMO
Vitamin D deficiency shows positive correlation to cardiovascular risk, which might be influenced by gender specific features. Our goal was to examine the effect of Vitamin D supplementation and Vitamin D deficiency in male and female rats on an important hypertension target organ, the renal artery. Female and male Wistar rats were fed with Vitamin D reduced chow for eight weeks to induce hypovitaminosis. Another group of animals received normal chow with further supplementation to reach optimal serum vitamin levels. Isolated renal arteries of Vitamin D deficient female rats showed increased phenylephrine-induced contraction. In all experimental groups, both indomethacin and selective cyclooxygenase-2 inhibition (NS398) decreased the phenylephrine-induced contraction. Angiotensin II-induced contraction was pronounced in Vitamin D supplemented males. In both Vitamin D deficient groups, acetylcholine-induced relaxation was impaired. In the female Vitamin D supplemented group NS398, in males the indomethacin caused reduced acetylcholine-induced relaxation. Increased elastic fiber density was observed in Vitamin D deficient females. The intensity of eNOS immunostaining was decreased in Vitamin D deficient females. The density of AT1R staining was the highest in the male Vitamin D deficient group. Although Vitamin D deficiency induced renal vascular dysfunction in both sexes, female rats developed more extensive impairment that was accompanied by enzymatic and structural changes.
Assuntos
Artéria Renal/fisiopatologia , Deficiência de Vitamina D/complicações , Vitamina D/administração & dosagem , Ração Animal/análise , Animais , Peso Corporal , Feminino , Masculino , Ratos , Ratos Wistar , Fatores SexuaisRESUMO
BACKGROUND: Several reports prove interconnection between vitamin D (VD) deficiency and increased cardiovascular risk. Our aim was to investigate the effects of VD status on biomechanical and oxidative-nitrative (O-N) stress parameters of coronary arterioles in rats. METHODS: 4-week-old male Wistar rats were divided into a control group (11 animals) with optimal VD supply (300 IU/kgbw/day) and a VD-deficient group (11 animals, <5 IU/kg/day). After 8 weeks, coronary arteriole segments were prepared. Geometrical, elastic, and biomechanical characteristics were measured by in vitro arteriography. O-N stress markers were investigated by immunohistochemistry. RESULTS: Inner radius decreased; wall thickness and wall-thickness/lumen diameter ratio increased; tangential wall stress and elastic modulus were reduced in VD-deficient group. No difference could be found in wall-cross-sectional area, intima-media area %. While the elastic elements of the vessel wall decreased, the α-smooth muscle actin (α-SMA) immunostaining intensity showed no changes. Significant elevation was found in the lipid peroxidation marker of 4-hidroxy-2-nonenal (HNE), while other O-N stress markers staining intensity (poly(ADP)ribose, 3-nitrotyrosine) did not change. CONCLUSIONS: Inward eutrophic remodeling has developed. The potential background of these impairments may involve the initial change in oxidative damage markers (HNE). These mechanisms can contribute to the increased incidence of the cardiovascular diseases in VD deficiency.
RESUMO
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.
Assuntos
Autofagia , Fígado/patologia , Ovário/patologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/patologia , Deficiência de Vitamina D/complicações , Animais , Proliferação de Células , Modelos Animais de Doenças , Feminino , Estresse Nitrosativo , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Receptores de Calcitriol/metabolismo , Transdução de SinaisRESUMO
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.
Assuntos
Androgênios/efeitos adversos , Hiperandrogenismo/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Testosterona/efeitos adversos , Deficiência de Vitamina D/fisiopatologia , Administração Oral , Androgênios/administração & dosagem , Androgênios/sangue , Animais , Artéria Cerebral Anterior , Dieta , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/complicações , Masculino , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Risco , Fatores Sexuais , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/etiologia , Testosterona/administração & dosagem , Testosterona/sangue , Vasoconstrição/efeitos dos fármacos , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/induzido quimicamente , Deficiência de Vitamina D/complicaçõesRESUMO
BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Arteríolas/fisiopatologia , Artérias Cerebrais/fisiopatologia , Remodelação Vascular , Deficiência de Vitamina D/fisiopatologia , Animais , Glicemia/metabolismo , Masculino , Ratos , Ratos Wistar , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
Hyperandrogenic state in females is accompanied with metabolic syndrome, insulin resistance and vascular pathologies. A total of 67%-85% of hyperandrogenic women suffer also from vitamin D deficiency. We aimed to check a potential interplay between hyperandrogenism and vitamin D deficiency in producing insulin resistance and effects on coronary resistance arteries. Adolescent female rats were divided into four groups, 11-12 animals in each. Transdermal testosterone-treated and vehicle-treated animals were kept either on vitamin D-deficient or on vitamin D-supplemented diet for 8 weeks. Plasma sexual steroid, insulin, leptin and vitamin D plasma levels were measured, and oral glucose tolerance test was performed. In coronary arterioles, insulin receptor and vitamin D receptor expressions were tested by immunohistochemistry, and insulin-induced relaxation was measured in vitro on isolated coronary resistance artery segments. Testosterone impaired glucose tolerance, and it diminished insulin relaxation but did not affect the expression of insulin and vitamin D receptors in vascular tissue. Vitamin D deficiency elevated postprandial insulin levels and homeostatic model assessment insulin resistance. It also diminished insulin-induced coronary arteriole relaxation, while it raised the expression of vitamin D and insulin receptors in the endothelial and medial layers. Our conclusion is that both hyperandrogenism and vitamin D deficiency reduce sensitivity of coronary vascular tissue to insulin, but they do it with different mechanisms.