Estriol attenuates visceral adiposity and pulmonary artery smooth muscle cell proliferation via ERα-mediated signalling

Aims: Estriol (E3) is a natural estrogen produced during pregnancy whose physiological role in the adult cardiovascular and pulmonary systems remains poorly understood. Given the established association between estrogens and obesity, our study aims to investigate the interplay between obesity, E3, and their potential cardiopulmonary effects. Methods and results: Effect of E3 on the cardiopulmonary system was evaluated in lean and high-fat diet-induced obese mice using right heart catheterization. Plasma triglyceride and adipokines were quantified using immunological assays, and circulating E3 levels were measured via LC-MS/MS. In vitro experiments were carried out in a human adipocyte cell line and pulmonary artery smooth muscle cells (PASMCs) isolated from rats and patients with pulmonary arterial hypertension. E3 reduces visceral adipose tissue mass in vivo, primarily by attenuating adipocyte inflammation and proliferation. E3 treatment significantly reduced plasma leptin levels, contributing to improved metabolic profiles. In adipocytes, E3 reduced pro-proliferation and inflammatory markers while increasing the expression of antioxidant genes. Additionally, E3 reduced proliferation in isolated PASMCs and E3-induced signalling was observed to be mediated through the ERα receptors. Conclusion: Our findings demonstrate, for the first time, that E3 reduces visceral adipose tissue mass, indicating its role in modulating adipose tissue characteristics while concurrently enhancing metabolic profiles. These results lay the groundwork for future research to investigate the role of E3 in disease prevention and its therapeutic application in cardiopulmonary disorders.