Gender-related small artery function: implications for estrogenic compounds

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Clinical Sciences

Sammanfattning: Background: Vascular effects of estrogens have been shown to be mediated by estrogen receptor (ER)?. The discovery of ER?, which shares many similarities with ER?, brought about a reevaluation of the role of the ER subtypes (ERs) in the vasculature. The resistance arteries play a key part in the control of peripheral resistance, and are ideally suited to control blood pressure and flow to target organs. Endothelial dysfunction is a halmark of cardiovascular disease (CVD) in both genders. Therefore, it is a major target in cardiovascular prevention. Aim: (1) to evaluate acute vascular effects of selective estrogenic compounds as phytoestrogens genistein and resveratrol (high affinity for ER?), ER? selective agonist PPT (propyl-pyrazoletriol), ERbeta agonist DPN (diarylpropionitrile) in resistance arteries from women and men with and without CVD and from ER? knockout (?ERKO) mice; (2) to compare the characteristics of small arteries between ?ERKO and wild-type (WT) mice, and their response to 17?-E2. Methodology: Subcutaneus arteries were obtained from patients of both genders with previous myocardial infarction and matched healthy controls. ?ERKO male and female mice and their WT littermates were included for isolation of small arteries. The Multi-Myograph was used to study acute effects of estrogenic compounds and for responses to endotheliumdependent agonist. The responses to flow, pressure-induced myogenic tone, agonists-induced dilatation, vasoconstriction and passive properties were assessed using a pressure-myograph. Endothelial morphology, distribution of ERs within the vascular wall, and collagen/elastin content were determined by immunohystochernistry and histological methods, in combination with scanning electron microscopy. Results and conclusions: (1) Estrogens, through the action of ER? may increase distensibility in the resistance vasculature of the female mouse. In the male mouse the same receptor modulates the control of estrogen-enhanced flow mediated dilation, whereas in the females, ER? is important for this response. In the male animals, deletion of ER? alters the content of elastin and collagen within the vascular wall. Myogenic tone is unaffected by the loss of ER? in either male or female mice, while gender specific differences occur in myogenic tone after administration of 17?-E2, indicating the importance of ER? in the modulation of basal tone in the female vasculature. (2) Acute dilatory responses induced by different estrogenic compounds in small femoral arteries were similar in WT and betaERKO mice of both genders, but differed mechanistically. ER? apparently inhibited ER?-mediated NO contribution suggesting an interaction between ERs and supporting the importance of ERs interplay in the maintenance of endothelial function. (3) Phytoestrogens evoked ex vivo acute dilatation in small arteries from men and women with CV1) and control subjects at concentrations attainable in vivo with consumption of soy-derived products/moderate red wine intake. The contribution of NO to acute dilation was evident in arteries from healthy men, whereas other NO-independent mechanism(s) were involved in arteries from CVD patients of both genders and control women. Pharmaceutical and/or diet supplementation by estrogenic compounds with higher selectivity for ER? may provide cardiovascular benefit for women with CVD, while compounds selective for ER? seemed to be of importance for healthy women. Significance: By using several approaches for the evaluation of resistance artery function, we have demonstrated the relative importance of each ER for the vascular health. Estrogenic compounds that selective bind to specific ERs might be an important therapeutic option for prevention and treatment of CVD.

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