Endothelial cells (ECs) are a highly specialized and heterogeneous population that plays a fundamental role in maintaining vascular homeostasis, immune regulation, and blood flow control. Beyond serving as a physical barrier, ECs exhibit remarkable plasticity, undergoing phenotypic transitions, including endothelial-to-mesenchymal (EndMT), endothelial-to-hematopoietic (EndHT), endothelial-to-osteoblast (EndOT) and endothelial-to-immune-cell-like (EndICLT). These transitions allow ECs to adapt to developmental, physiological, and pathological conditions. Advances in single-cell RNA sequencing (scRNA-seq), and associated technologies, have provided deeper insights into the molecular diversity of ECs across different vascular beds and stages of development, revealing their transcriptional heterogeneity and specialized functions. For example, ECs within the aortic arch display distinct phenotypic variations depending on their location, reflecting adaptations to regional differences in blood flow and shear stress. Activated EndMT has been implicated in the progression of various cardiovascular diseases, including hypertension, atherosclerosis, and vascular malformations by contributing to endothelial dysfunction, vascular wall inflammation, and remodeling. Recent therapeutic approaches aim to mitigate EndMT-associated vascular damage through interventions such as endothelial reprogramming, statins, and autophagy enhancers. Partial reprogramming of ECs has shown promise in restoring endothelial function, reducing vascular stiffness, and lowering blood pressure in hypertensive models. Understanding the complexity of EC heterogeneity and plasticity is critical for developing targeted therapies to prevent and treat cardiovascular diseases. By leveraging emerging genomic technologies and reprogramming strategies, future research may offer novel regenerative medicine approaches to restore vascular health and improve clinical outcomes for patients with cardiovascular diseases.