Alteration of endothelial estrogen receptor (ER)alpha with ageing : consequences for women arterial protection – ArtER

Arterial aging is characterized by endothelial dysfunction and arterial stiffening that contribute to the development of atherosclerosis and hypertension, two major causes of cardiovascular disease (CVD). In women, this risk is increased at menopause due to the cessation of ovarian production of estradiol (E2), which can no longer exert its beneficial effects on the arteries. It is not clear to what extent the cardiovascular protection afforded by endogenous estrogens can be prolonged by the administration of exogenous estrogens. Unexpectedly, the results of the Women's Health Initiative (WHI) study of menopausal hormone therapy showed that conventional exogenous estrogen does not protect against cardiovascular disease. In addition, this study confirmed the thromboembolic and breast cancer risk associated with this treatment. However, subsequent age-specific analyses showed that hormone therapy conferred cardiovascular protection if given early (in the first 10 years after menopause), but not late in older women. This underscores the need to better understand the interaction between age and estrogen action, given that most experimental studies have been conducted in young animal models. The bad publicity surrounding the WHI study led to a drastic decrease in menopause treatment, with adverse consequences on women quality of life. In this context, Estetrol (E4), a natural estrogen produced during pregnancy, is currently developed as a new hormonal treatment for menopause. Because of its minimal impact on the liver, E4 could not increase the risk of thromboembolism.

Previous work by the consortium involved in the ArtER project has shown that E2 and E4 have similar arterial protective actions in young ovariectomized mice by activating the estrogen receptor (ER)a. Although some of the vascular protection of E2 is mediated by membrane ERa in endothelial cells, E4 acts through nuclear ERa primarily in smooth muscle cells. Our preliminary results also indicate that in contrast to its beneficial effect in young mice, E2 does not accelerate endothelial healing in mid-life mice, whereas the effect of E4 is preserved.

In the ArtER project, we now propose to investigate the hypothesis that the specific activation profile of E4 would provide more sustained global arterial protection with aging than conventional estrogens. To this end, the ArtER project will be organized into 4 work packages:
1/ To establish the effect of aging on ERa expression/action in female mouse arteries, in particular, the fate of nuclear versus membrane ERa signaling pathways.
2/ To understand the differential mechanisms of E2 and E4 action on arteries during aging using large-scale transcriptomic, cistromic and epigenetic approaches.
3/ To define the extent of arterial protection by E4 (compared with E2) in mid-life mice by assessing i) vascular reactivity and pathways of vasodilation, ii) protection against angiotensin II induced hypertension and iii) prevention against atherosclerosis.
4/ To study the counterpart of these results obtained in mice to female tissues thanks to a biobank of more than a hundred aortas from women aged 14 to 88 years already available.

Ultimately, the arterial protection benefit of E4 would be added to its neutrality in terms of thromboembolic risk. The ArtER project could thus lead to proposing E4 as a safer option for the management of menopause and reconcile women with hormone treatment. In addition to improving women's health, optimizing this treatment would help reduce the emotional burden and social stigma associated with menopause.