Estetrol (E4), a estrogen of fetal origin, does not always activate the same mechanisms as the hormones currently used in the treatment of menopausal symptoms or for oral contraception. The work carried out in Toulouse by a team Inserm indeed suggest that it would have a protective effect on the vessels.
Estradiol (also called E2) is the main estrogen secreted by the ovaries of women of childbearing age. At menopause, the production of this female hormone drops, resulting in major upheavals: hot flashes, sleep disorders, mood disorders, genitourinary disorders, etc. This hormonal change also increases the risk of developing pathologies such as osteoporosis or cardiovascular disease. Also, hormonal treatment of menopause (THM) based on estrogen is offered to the women concerned. However, the balance between the benefits and the risks of this treatment is controversial, in particular because it increases the risk of thrombosis venous – a risk that also exists with oral administration of estrogen (ethinylestradiol) used as a contraceptive. In order to avoid these undesirable effects and to contribute to the development of safer hormonal treatments for women, Inserm researcher Coralie Fontaine and her team at the Institute of Metabolic and Cardiovascular Diseases in Toulouse are exploring the molecular and cellular mechanisms that depend on of the estrogen.
The main alternative to estradiol is currently estetrol (E4), a natural estrogen produced by the fetal liver during pregnancy. It is now being evaluated as a THM potential within the framework of clinical studies. The Toulouse team uses the mouse model to study its effects on the arteries, in comparison with those of E2. The researchers observed that the two hormones accelerate the healing of lesions in the vascular wall, but that they act via different cellular targets and mechanisms.
An estrogen receptor ubiquitous
Their work shows that if these two estrogens bind to the same receptor, called ERa, this interaction does not translate in the same way because ERa is ubiquitous: it is present in the cell nucleus, where it modulates the expression of certain genes. , but also outside the nucleus, at the level of the cytoplasm or the cell membrane, where it directly modulates different cellular processes. “ We observed that the stimulation of vascular healing by E4 does not go through a direct action on ER receptorsa damaged cell membranes, as is the case with E2. It acts on the nuclear receptors smooth muscle cells that form the inner layer of vessels”, explains the researcher. It is therefore the cells neighboring the lesions that promote vascular healing once their ERa receptors are activated: E4 has an indirect action on the vessel wall (known as “paracrine”) that is not found with other estrogens .
It has already been demonstrated that E4 would limit the thromboembolic risk because it has little or no impact on the coagulation factors of hepatic origin, unlike E2. This study suggests that it would provide an additional benefit by promoting the integrity of the layer of cells that line the inside of the arteries, thus protecting them. ” Since the arterial risk linked to estrogens evolves with the age of women, we now want to conduct these same studies on vessels taken from older mice. This work will ensure that the beneficial properties of E4 are retained after menopause “, concludes Coralie Fontaine.
Coralie Fontaine co-leads the team Estrogen receptor: vascular, metabolic and endocrine dysfunctions (ESTER) with Françoise Lenfant at the Institute of Metabolic and Cardiovascular Diseases (I2MC, Inserm unit 1297/Toulouse III – Paul-Sabatier University), in Toulouse.
Source : M. Davezac et coll. The different natural estrogens promote endothelial healing through distinct cell targets. JCI Insight, edition of February 2, 2023; doi: 10.1172/jci.insight.161284