RESUMEN
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.
Asunto(s)
Andrógenos/efectos adversos , Hiperandrogenismo/fisiopatología , Accidente Cerebrovascular/fisiopatología , Testosterona/efectos adversos , Deficiencia de Vitamina D/fisiopatología , Administración Oral , Andrógenos/administración & dosificación , Andrógenos/sangre , Animales , Arteria Cerebral Anterior , Dieta , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Hiperandrogenismo/sangre , Hiperandrogenismo/inducido químicamente , Hiperandrogenismo/complicaciones , Masculino , Ratas , Ratas Wistar , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Riesgo , Factores Sexuales , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/etiología , Testosterona/administración & dosificación , Testosterona/sangre , Vasoconstricción/efectos de los fármacos , Vitamina D/administración & dosificación , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/inducido químicamente , Deficiencia de Vitamina D/complicacionesRESUMEN
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.
Asunto(s)
Arteriolas/fisiopatología , Arterias Cerebrales/fisiopatología , Remodelación Vascular , Deficiencia de Vitamina D/fisiopatología , Animales , Glucemia/metabolismo , Masculino , Ratas , Ratas Wistar , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
OBJECTIVE: Hypertension causes adverse remodeling and vasomotor alterations in coronaries. Hormones such as estrogen may help counterbalance some of these effects. The aim of this study was to analyze the effects of ovariectomy and estrogen therapy in a rat model of menopausal hypertension induced by angiotensin II (AII). METHODS: We investigated diameter, tone, and mechanics of intramural coronaries taken from ovariectomized female rats (nâ=â11) that received chronic AII treatment to induce hypertension, and compared the results with those found in female rats that were also given estrogen therapy (nâ=â11). The "hypertensive control" group (nâ=â11) underwent an abdominal sham operation, and received AII. After 4 weeks of AII treatment, side branches of left anterior descendent coronary (approximately 200âµm in diameter) were isolated, cannulated with plastic microcannulas at both ends, and studied in vitro in a vessel chamber. The inner and outer diameter of the arteries were measured by microangiometry, and spontenuous tone, wall thickness, wall cross-sectional area, tangential stress, incremental distensibility, circumferential incremental elastic modulus, thromboxane agonist-induced tone, and bradykinin-induced dilation were calculated. RESULTS: In hypertension, intramural small coronaries show inward eutrophic remodeling after ovariectomy comparing with hypertensive controls. Estrogen therapy had an opposite effect on vessel diameter. Hormone therapy led to an increase in spontaneous tone, allowing for greater dilatative capacity. CONCLUSIONS: Estrogen may therefore be considered to counterbalance some of the adverse changes seen in the wall of intramural coronaries in the early stages of chronic hypertension.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Estrógenos/farmacología , Hipertensión/tratamiento farmacológico , Menopausia , Remodelación Vascular/efectos de los fármacos , Angiotensina II , Animales , Bradiquinina/farmacología , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Terapia de Reemplazo de Estrógeno/métodos , Femenino , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Vasoconstrictores , Vasodilatadores/farmacologíaRESUMEN
Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3 (vitD). PCOS was induced in female Wistar rats by DHT treatment (83 µg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine-induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of N(G)-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration.
Asunto(s)
Colecalciferol/farmacología , Extremidad Inferior/irrigación sanguínea , Síndrome del Ovario Poliquístico/fisiopatología , Vena Safena/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Ciclooxigenasa 2/metabolismo , Dihidrotestosterona , Modelos Animales de Enfermedad , Femenino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Ratas , Ratas Wistar , Vena Safena/metabolismo , Vena Safena/patología , Vena Safena/fisiopatología , Vasoconstrictores/farmacología , Vasodilatadores/farmacología , Presión Venosa/efectos de los fármacosRESUMEN
The aim of this study was to clarify the effects of dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS) on pharmacological reactivity of a resistance vessel in a rat model and the possible modulatory role of 1,25-(OH)2-cholecalciferol (vitamin D3). The PCOS model was induced in adolescent female Wistar rats by a 10-week DHT treatment. Norepinephrine induced contractility and acetylcholine relaxation were tested in arterioles by pressure arteriography in control as well as DHT- and DHT plus vitamin D3-treated (DHT+D3) animals. Decreased vasoconstriction and dilatation were detected after DHT treatment. Concomitant vitamin D3 treatment increased the contractile response and resulted in more relaxed vessels. Endothelial dilation tested with acetylcholine was lower after DHT treatment, this effect was not depend on vitamin D3 supplementation. In conclusion, hyperandrogenic state resulted in reduced endothelium- and smooth muscle-dependent vasorelaxation and constriction with a complete loss of nitric oxide (NO)-dependent relaxation compared with controls. These alterations caused by chronic DHT treatment were partially reversed by concomitant vitamin D3 administration.