BACKGROUND: Endostatin (ES) is an endogenous angiogenesis inhibitor. It is confirmed that ES has antitumor effects and plays a crucial part in regulating vascular smooth cells' proliferation. However, ES's effect on pulmonary hypertension (PH) is unclear. The aim of this study was to determine the effect of ES on PH's pathogenesis. METHODS: PH was induced by pneumonectomy plus monocrotaline (MCT) injection, as indicated with significantly increased pulmonary arterial pressure and vascular wall thickness. RESULTS: Immunohistochemical analysis showed that under physiological conditions, ES localized in endothelial cells (ECs) and spread to the muscular vascular layers in PH rats. ES was transfected into the lungs of rats intratracheally 2 weeks after MCT injection. Consequently, ES not only reduced elevated VEGF's expression but also reversed pulmonary artery remodeling. Eventually, ES improved elevated right ventricular (RV) mean pressure and RV hypertrophy. CONCLUSIONS: The administration of ES may be a new treatment for PH and PA remodeling, associating with the downregulation of VEGF production.