CES1 deficiency is associated with metabolic reprograming and endothelial dysfunction in pulmonary arterial hypertension

Abstract Rationale Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling driven by endothelial dysfunction. Low penetrance of only bone morphogenetic protein receptor 2 (BMPR2) mutations causing metabolic shifts in pulmonary microvascular endothelial cells (PMVECs) suggests a role of additional genetic modifiers. Genetic screening of PAH PMVECs identified carboxylesterase 1 (CES1)—an endoplasmic reticulum (ER) enzyme involved in lipid metabolism and detoxification—as a candidate regulator of endothelial metabolism and angiogenesis. We hypothesize that CES1 loss promotes endothelial dysfunction via metabolic reprogramming, lipotoxicity, and oxidative stress. Methods PAH/healthy PMVECs and lung tissues were obtained from transplant donors and commercial sources. CES1 knockdown and CES1 overexpression was performed in PMVECs for functional assays. Animal studies were done on CES1 heterozygous knockout (HET-KO) and endothelial-specific knockout (ECKO) mice exposed to normoxia or hypoxia. Measurements and Main Results CES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species production, mitochondrial fragmentation, ER stress, and impaired angiogenesis. CES1 loss caused lipid droplet accumulation, reduced fatty acid oxidation, and glycolytic shift—phenotypes reversed by CES1 restoration. CES1 transcription was induced by BMPR2 via NRF2 activation, a key regulator of redox and metabolic homeostasis. CES1-deficient mice developed severe pulmonary hypertension under hypoxia, with extensive vascular remodeling, right ventricular dysfunction, and dysregulated angiogenesis and lipid metabolism pathways. Conclusions CES1 is essential for pulmonary endothelial homeostasis and modifier of BMPR2 signaling. Restoring CES1 expression may serve as potential therapeutic strategy in reversing endothelial dysfunction and small-vessel loss.