Apolipoprotein M: Structural insights, functional roles, and therapeutic approaches in vascular disease

Apolipoprotein M (ApoM) is a lipocalin predominantly associated with high-density lipoprotein (HDL) that transports sphingosine-1-phosphate (S1P) in circulation. Through its stable binding and selective delivery of S1P to the endothelial S1P receptors (S1PRs), ApoM orchestrates a spectrum of vasoprotective effects. This review summarizes the structural characteristics of ApoM and its unique function as a sphingolipid chaperone, focusing on its role in vascular biology, specifically endothelial barrier integrity, vascular tone, and inflammation. We examine the biased signaling of ApoM-HDL-S1P through S1PR1 and its implications in modulating nitric oxide production and endothelial adherens junction assembly. In addition, circulating ApoM⁺-HDL appears to be important in transendothelial HDL transport and cholesterol efflux. Clinical and preclinical studies have linked reduced ApoM expression with cardiometabolic diseases, such as obesity, insulin resistance, type 2 diabetes, and chronic kidney disease, while emerging evidence also implicates ApoM in neurovascular, inflammatory, and retinal disorders. ApoM expression and plasma levels are regulated by hepatocyte nuclear factors, Forkhead box O nuclear transcription factors and inflammatory cytokines but also pharmacologically by statins and SGLT2 inhibitors. Recent development of engineered ApoM-based biologics, such as ApoM-Fc and ApoA1-ApoM fusion proteins, shows promise in preclinical models of vascular disease, demonstrating improvements in endothelial function, inflammation, and pathological neovascularization without inducing immunosuppression or bradycardia. Collectively, these insights position ApoM as both a critical biomarker and a therapeutic target for vascular health. Advancing ApoM-based therapies may offer a novel precision medicine strategy to treat cardiovascular and metabolic diseases through endothelial-targeted modulation of S1P signaling.