Stuti Agarwal, Anuradha Bankar, Lyong Heo, Ankita Mitra, Ananya Chakraborty, Lichao Liu, Flora Huang, Gowri Swaminathan, Natasha Auer, Prakash Chelladurai, Eleana Stephanie Guardado, Juan Matos, Crystal Le, James West, Karthik Suresh, Ramesh Nair, Marlene Rabinovitch, Christophe Morisseau, Bruce D Hammock, Joseph Wu, Zolt Arany, Mark R Nicolls, Vinicio de Jesus Perez
Stanford Center for Genomics and Personalized Medicine and Stanford University. Vanderbilt University Medical Center. Johns Hopkins Bayview Medical Center. University of Pennsylvania Perelman School of Medicine. VA Palo Alto Health Care System.
United States
American Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med 2026;
DOI: 10.1093/ajrccm/aamag077
Abstract
Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling driven by endothelial dysfunction. Low penetrance of only BMPR2 mutations causing metabolic shifts in pulmonary microvascular endothelial cells (PMVECs), suggests role of additional genetic modifiers. Genetic screening of PAH PMVECs identified carboxylesterase1 (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.
Results: CES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species (ROS) 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 (PH) 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.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes