Sex differences in cardiovascular disease: mechanistic insights from in vitro models

Abstract Background Biological sex is a fundamental determinant of the pathogenesis and progression of cardiovascular disease (CVD). ​Despite extensive research on sex differences in human populations and whole-animal preclinical models, studies directly comparing male- and female-derived cells within defined cardiovascular cell types remain limited. Although human and in vivo studies have clearly highlighted the importance of sex differences, their complex systemic environments can make it difficult to disentangle cell-associated effects from the effects of circulating hormones and interactions among multiple cell types. Accordingly, this narrative review integrates evidence primarily from studies of isolated cardiovascular cells, supplemented where appropriate by relevant in vivo and clinical findings, to examine the reported contributions of hormonal signaling, sex chromosome complement, and related pathophysiological mechanisms. Main body The reviewed studies report sex-associated cellular differences related to hormonal signaling and, in specific experimental models, sex chromosome complement. Across three major pathophysiological domains—oxidative stress, nitric oxide signaling, and inflammatory responses—the direction and magnitude of the reported differences vary according to cell type, tissue or vascular origin, species, and experimental conditions. Conclusion Collectively, this review provides an integrated overview of reported sex-associated differences in cardiovascular cells and the hormonal, chromosomal, and pathophysiological factors that may contribute to them. The available evidence highlights the need for further direct male–female comparisons at the cellular level relevant to CVD, while complementary multicellular and in vivo approaches remain necessary to determine the relevance of cellular findings at the tissue and organ levels. Such studies may provide a stronger foundation for developing sex-informed precision therapies for CVD.