Endothelial cell metabolic reprogramming and pulmonary hypertension: Research progress and therapeutic potential

Pulmonary hypertension (PH) is a progressive and life-threatening cardiovascular disorder characterized by elevated pulmonary arterial pressure and pulmonary vasculature remodeling. Accumulating evidence highlights that metabolic reprogramming in pulmonary arterial endothelial cells (PAECs) as a fundamental driver of PH initiation and progression. This metabolic shift involves a transition to a hyper-glycolytic state, disordered fatty acid oxidation, and increased glutaminolysis, which contributes significantly to the pathogenesis of PH. Oxidative stress and mitochondrial dysfunction triggered by metabolic alterations in PAECs, establishing a self-reinforcing cycle of damage that disrupts vascular homeostasis. Furthermore, metabolic reprogramming drives PAECs heterogeneity, leading to the emergence of pathogenic subpopulations, including pro-inflammatory ECs, senescent ECs, and mesenchymal-like ECs via endothelial-to-mesenchymal transition (EndoMT). In addition to intrinsic changes, metabolically dysregulated ECs initiate aberrant intercellular crosstalk with smooth muscle cells, immune cells, and fibroblasts through the secretion of cytokines, lactate, and extracellular vesicles, ultimately accelerating vascular structural remodeling. In this review, we discussed the feasibility of targeting the metabolic drivers, such as inhibiting glycolysis, restoring mitochondrial function, or modulating amino acid metabolism in ECs, which have shown potential in preclinical and early clinical studies to alleviated PH. This offers new perspectives for the development of novel therapeutic strategies for PH.