Sex differences in endothelial cell biology: cellular phenotypes and molecular regulators

Endothelial cells (EC) line all blood vessels and are central to maintaining vascular homeostasis by regulating barrier integrity, angiogenesis, inflammation and other key processes. Although EC share core functions, they exhibit substantial heterogeneity across vascular beds and tissues, reflecting differences in local metabolic and microenvironmental conditions. Emerging evidence indicates that endothelial biology is also shaped by sex. Male and female EC differ in multiple aspects of cellular physiology, including metabolic activity, nitric oxide signaling, angiogenic capacity, oxidative stress responses, inflammatory signaling, and susceptibility to senescence. In this review, we summarize the current knowledge of these sex-dependent EC phenotypes and discuss how they vary by vascular location, as well as across age and disease context. Increasing evidence suggests that these differences arise from a complex interplay between sex hormones, sex chromosome complement, epigenetic regulation, and transcription factor networks. We discuss recent advances in understanding these mechanisms and their contributions to EC heterogeneity. Recognizing sex-specific EC functional characteristics and vulnerabilities is critical for a comprehensive understanding of vascular physiology and pathology, with important implications for improved knowledge of vascular disease mechanisms and development of more precise, sex-informed therapeutic strategies.