Gender-related small artery function : implications for estrogenic compounds

Background: Vascular effects of estrogens have been shown to be mediated by estrogen receptor (ER)α. The discovery of ERβ, which shares many similarities with ERα, 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 ERβ), ERα selective agonist PPT (propyl-pyrazoletriol), ERbeta agonist DPN (diarylpropionitrile) in resistance arteries from women and men with and without CVD and from ERβ knockout (βERKO) mice; (2) to compare the characteristics of small arteries between βERKO and wild-type (WT) mice, and their response to 17β-E2.

Methodology: Subcutaneus arteries were obtained from patients of both genders with previous myocardial infarction and matched healthy controls. βERKO 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 ERβ 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, ERα is important for this response. In the male animals, deletion of ERβ alters the content of elastin and collagen within the vascular wall. Myogenic tone is unaffected by the loss of ERβ in either male or female mice, while gender specific differences occur in myogenic tone after administration of 17β-E2, indicating the importance of ERα 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. ERβ apparently inhibited ERα-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 ERβ may provide cardiovascular benefit for women with CVD, while compounds selective for ERα 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.

List of scientific papers

I. Douglas G, Cruz MN, Gustafsson JÅ, Poston L, Kublickiene K (2006). Functional characterization and gender differences in small mesenteric arteries of the estrogen receptor beta knockout mouse. [Submitted]

II. Cruz MN, Douglas G, Gustafsson JA, Poston L, Kublickiene K (2006). Dilatory responses to estrogenic compounds in small femoral arteries of male and female estrogen receptor-beta knockout mice. Am J Physiol Heart Circ Physiol. 290(2): H823-9.
https://pubmed.ncbi.nlm.nih.gov/16183727

III. Cruz MN, Luksha L, Logman H, Poston L, Agewall S, Kublickiene K (2005). Acute responses to phytoestrogens in small arteries from men with coronary heart disease. Am J Physiol Heart Circ Physiol. 290(5): H1969-75.
https://pubmed.ncbi.nlm.nih.gov/16361368

IV. Cruz MN, Agewall S, Shenck-Gustafsson K, Kublickiene K (2006). Acute dilatation to phytoestrogens and estrogen receptor subtypes expression in small arteries from women with coronary heart disease. [Submitted]