Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice

Journal of the American Heart Association - Tập 9 Số 5 - 2020
E. Guivarch1, Julie Favre1, Anne‐Laure Guihot1, Emilie Vessières1, Linda Grimaud1, C Proux1, J Rivron1, Agnès Barbelivien1, Céline Fassot1, Marie Briet1,2, Françoise Lenfant3, Coralie Fontaine3, Laurent Loufrani1, Jean‐François Arnal3, Daniel Henrion1,2
1MITOVASC Institute and CARFI Facility INSERM U1083 CNRS UMR 6015 Angers University Angers France
2University Hospital of Angers, Angers, France
3Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse 3 UMR INSERM 1048 Toulouse France

Tóm tắt

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane‐initiated signaling. The latter plays a key role in estrogen‐dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women.

Methods and Results Five‐ and 18‐month‐old female mice lacking either ERα (ERα −/− ), the nuclear activating function AF2 of ERα (AF2°), or membrane‐located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα −/− and AF2° mice more than in wild‐type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium‐dependent relaxation in all groups, but this effect was more pronounced in ERα −/− and AF2° than in the wild‐type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα −/− and AF2° than in old hypertensive wild‐type and C451A mice.

Conclusions The nuclear ERα‐AF2 dependent function attenuates angiotensin II–dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

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Journal of the American Heart Association

Tập 9 Số 5

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