Preprints.org · Oct 19, 2026

Estrogen Signaling in Cardiovascular Health and Disease: Molecular Mechanisms, Genetic Modifiers, and Therapeutic Translation

By Aguilar-Garrido L, García-López V, Lopez-Sanchez C et al.

Cardiovascular disease displays marked sex-related heterogeneity across the life course, and the rise in cardiometabolic and vascular risk during the menopausal transition has focused attention on estrogen signaling. Healthy female hearts are not simply scaled-down male hearts; population averages differ in cardiac mass, chamber geometry, myocardial deformation, hemodynamics, and repolarization. This narrative review integrates experimental, epidemiological, genetic, and clinical evidence on estrogen action in the cardiovascular system. Estrogens signal through ERalpha and ERbeta, their membrane-associated pools, and GPER, whereas estrogen-related receptors coordinate overlapping metabolic programs without binding estrogen. These pathways regulate endothelial nitric oxide production, redox balance, inflammation, mitochondrial energetics, autophagy, calcium handling, electrophysiology, extracellular-matrix remodeling, and non-coding RNA networks. Their effects depend on cell type, age, receptor abundance, vascular substrate, comorbidities, and genetic or epigenetic variation. This context dependence helps explain why endogenous estrogen exposure cannot be equated with menopausal hormone therapy. Current evidence does not support hormone therapy for primary or secondary cardiovascular prevention; treatment of menopausal symptoms requires individualized assessment of indication, timing, formulation, route, thrombotic risk, and baseline cardiovascular health. Future studies should combine sex-aware human models, longitudinal multi-omics, and validated biomarkers to link estrogen-pathway variation with clinically meaningful cardiovascular outcomes.

doi.org/10.20944/preprints202610.1677.v1Open accessMechanisms