Endothelial Dysfunction in Sex-Specific Disparities in Cardiovascular Diseases: Biological Mechanisms, Diagnostic-Therapeutic Differences, and Translational Medicine Strategies

Abstract

Sex-specific disparities in the pathogenesis and outcomes of cardiovascular diseases (CVDs) highlight critical gaps in current clinical paradigms, particularly regarding endothelial dysfunction as a pivotal mediator of such differences. Males have a higher incidence of atherosclerosis-related CVD, while postmenopausal females experience microvascular dysfunction due to estrogen loss and androgen dominance. Estrogen confers cardioprotective effects via nitric oxide (NO)-mediated vasodilation and antioxidant pathways. In contrast, androgens exert dual pathological effects by promoting inflammation and oxidative stress in a concentration-dependent manner. Clinically, men develop obstructive coronary disease, whereas women present with underdiagnosed microvascular ischemia due to sex-neutral thresholds. Sex-specific risks (e.g., smoking/diabetes in women) and treatment disparities persist in CVDs, meaning sex-stratified diagnostics/therapeutics and trial reforms are needed to advance precision cardiology. Unlike traditional reviews that focus on mechanisms, this study aims to link molecular insights with translational strategies by proposing endothelial-targeted therapies, sex-adjusted diagnostic algorithms, and policy-driven trial reforms. By prioritizing the endothelial–sex hormone crosstalk as the nexus of pathophysiology and clinical translation, this synthesis advances precision cardiology beyond conventional symptom-focused paradigms.