Annexins: gatekeepers of endothelial homeostasis and dysfunction

The vascular endothelium plays a central role in maintaining tissue and vascular homeostasis by continuously adapting to biochemical, mechanical, and inflammatory stimuli from its environment. When this adaptive capacity is compromised, endothelial dysfunction develops, driving the onset and progression of a wide range of cardiovascular, metabolic, neurovascular, and inflammatory diseases. Although the molecular mechanisms underlying endothelial dysfunction are complex, growing evidence points to annexins as important regulators of endothelial responses under both physiological and pathological conditions. Annexins are a family of evolutionarily conserved Ca 2+ -dependent phospholipid-binding proteins best known for their roles in membrane organization and cellular signaling. Over the last decade, their functions have expanded considerably, revealing their involvement in processes that are fundamental for endothelial integrity and vascular homeostasis. Emerging studies indicate that annexins influence how endothelial cells respond to inflammatory, oxidative, metabolic, and mechanical stress, thereby shaping vascular barrier function, immune-inflammatory cell recruitment, thrombosis, and tissue repair. In this review, we discuss the current understanding of annexin family members in endothelial biology and examine their contribution to endothelial dysfunction across different disease settings. The available evidence highlights a complex and highly context-dependent network in which individual annexins can either preserve endothelial homeostasis or promote vascular injury depending on the cellular environment and pathological stimulus. A better understanding of their isoform-specific functions may not only advance our knowledge of endothelial pathophysiology but also identify new opportunities for the development of therapeutic strategies targeting inflammatory vascular diseases.