Human Umbilical Vein Endothelial Cells (HUVECs) in Pharmacology and Toxicology: A Review

ABSTRACT Endothelial cells (ECs) are interior surface cells covering blood vessels, which play a crucial role in maintaining vascular homeostasis. In vascular pharmacology and toxicology, ECs directly contact drugs or toxicants entering circulation. Therefore, the bio‐effects of pharmacological/toxicological substances on ECs have gained extensive research interest, which needs to be evaluated by reliable models. Human umbilical vein endothelial cells (HUVECs) have been served as versatile platforms to mimic diverse pathophysiological processes in vitro, stemming from their unique fetal arterial‐like exposure microenvironment, expression of key EC markers, and comparable EC responses to various pathophysiological stimuli. This review provides an overview of the application of HUVECs in pharmacology and toxicology, with a focus on their utility and limitations. HUVECs have been widely used to model the effects of pharmacological or toxicological substances on material exchange, barrier functions, cell death, endothelial nitric oxide synthase (eNOS) uncoupling, and EC dysfunction, angiogenesis, and thrombosis. However, their applicability is constrained primarily due to vascular‐type and organ‐specific heterogeneity. The review highlights key mechanisms investigated using HUVECs, including oxidative stress, inflammation, organelle damage, and autophagy, metabolic reprogramming (endometabolism), and epigenetic regulation. Strategies to overcome HUVECs' limitations, such as microfluidic techniques, co‐culture, and organoid models, are discussed. Finally, future directions are outlined, emphasizing the integration of HUVECs into multi‐scale models, dynamic microenvironment simulations, artificial intelligence (AI)‐assisted big data analysis, and patient‐derived ECs for precision toxicology and personalized medicine. This review aims to guide researchers in optimizing the use of HUVECs in pharmacological and toxicological studies.