Introduction/Background: While ubiquitination of proteins plays an important role in the development of pulmonary arterial hypertension (PAH), little is known about the role of deubiquitinases (DUBs) and, more specifically, ubiquitin carboxyl-terminal esterase-L1 (UCHL1), in this process. Our prior work reported that reductions in endothelial UCHL1 lead to increased degradation and reduced activated levels of Akt1. Given the pathologic role of Akt1 in PAH, we now hypothesize that endothelial UCHL1 deficiency leads to reductions in activated Akt1, resulting in the attenuation of PAH. Methods/Results: Tissues from animal PH models, as well as human PA endothelial cells (hPAEC) from patients with PAH, exhibited increased vascular staining and protein expression of UCHL1. Inhibition of UCHL1 in cell culture reduced vascular endothelial growth factor (VEGF)-induced angiogenesis, proliferation and migration of hPAECs. Endothelial-specific Uchl1 knockout mice ( Uchl1 EC-/- ) demonstrated reduced right ventricular hypertrophy (RVH), RV systolic pressures (RVSP), and improved right heart function compared to control mice exposed to chronic hypoxia. Consistent with these findings, histologic examination revealed significantly improved vascular medial thickness and remodeling as well as reduced total and activated Akt1 levels in the lungs of hypoxia-exposed Uchl1 EC-/- mice compared to hypoxia-exposed control mice. Conclusions: Our findings reveal that a specific deficiency of Uchl1 in the endothelium results in PAH attenuation via reduced Akt1, highlighting a novel therapeutic target.