Original ArticleInhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II ExpressionZheng, Yaguo MD*,†; Ma, Hong MD*,‡; Hu, Enci MD*; Huang, Zhiwei MD*; Cheng, Xiaoling MD*; Xiong, Changming MD, PhD*Author Information *State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; †Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China; and ‡Department of Echocardiography, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Reprints: ChangMing Xiong, MD, PhD, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi road, Beijing, 100037, China (e-mail: firstname.lastname@example.org). This work was supported by a national grant from the Ministry of Science and Technology (Project number: 2011BAI11B16). The authors report no conflicts of interest. Received March 26, 2015 Accepted July 22, 2015 Journal of Cardiovascular Pharmacology: November 2015 - Volume 66 - Issue 5 - p 504-514 doi: 10.1097/FJC.0000000000000302 Buy Metrics Abstract Background: Numerous studies have demonstrated that fibroblast growth factor-2 (FGF-2) signaling may play a pivotal role in the development of pulmonary arterial hypertension (PAH). Excessive endothelial FGF-2 contributes to smooth muscle hyperplasia and disease progression. PD173074 is a potent FGF receptor 1 (FGFR-1) inhibitor that displays high activity and selectivity. The aim of this study was to investigate the effects of PD173074 on monocrotaline-induced PAH. We also evaluated whether FGFR-1 inhibition could attenuate bone morphogenetic protein type II receptor (BMPR-II) downregulation in the monocrotaline model. Methods: PAH model was established by a single intraperitoneal injection of monocrotaline. And then a daily intraperitoneal injection of PD173074 (20 mg/kg) was administered from day 14 to day 28. Hemodynamic parameters, right ventricular hypertrophy index and morphometry were evaluated at day 28. Western blot and immunohistochemical analyses were used to determine the expression of FGF-2 and bone morphogenetic protein signaling in the lung tissue. Results: The expression of FGF-2 and FGFR-1 was upregulated in lung tissue after monocrotaline injection and it was accompanied by hemodynamic changes and pulmonary vascular remodeling. PD173074 treatment ameliorated PAH and vascular remodeling. It decreased ERK1/2 activation and rescued total Akt expression, leading to a reduction in both proliferation and apoptosis in the lung. Besides, PD173074 rescued the expression of BMPR-II and p-Smad 1/5/8. Conclusion: These results suggest that PD173074 can alleviate monocrotaline-induced pulmonary arterial hypertension and it may be a useful option for PAH. Our data also suggest a role of FGF-2/bone morphogenetic protein signaling interaction in PAH. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.