Dysregulation of BMP9/BMPR2/SMAD signalling pathway contributes to pulmonary fibrosis and pulmonary hypertension induced by bleomycin in rats

• DOI: 10.1111/bph.15285
• Publication Date: 2020-10-20T19:28:23Z
• Authors: Qian Jiang; Chunli Liu; Shiyun Liu; Wenju Lu; Yi Li; Xiaoyun Luo; Ran Ma; Chenting Zhang; Haixia Chen; Yuqin Chen; Zizhou Zhang; Cheng Hong; Wenliang Guo; Tao Wang; Kai Yang; Jian Wang
• Keywords: Male; 0301 basic medicine; Hypertension, Pulmonary; Pulmonary Fibrosis; Endothelial Cells; Pulmonary Artery; Bone Morphogenetic Protein Receptors, Type II; Rats; 3. Good health; Rats, Sprague-Dawley; Bleomycin; 03 medical and health sciences; Animals

Background and PurposePulmonary hypertension related to pulmonary fibrosis is classed as WHO Group III, one of the most common groups which lacks effective treatment options. In this study, we aimed to uncover the underlying mechanisms, particularly the involvement of the BMP9/BMPR2/SMAD signalling pathway, in this subtype of pulmonary hypertension.Experimental ApproachMale Sprague Dawley rats were used to establish a model of pulmonary hypertension with pulmonary fibrosis, induced by bleomycin. Haemodynamic and lung functions were measured, along with histological and immunohistochemical examinations. Primary cultures of rat pulmonary microvascular endothelial cells (PMVECs) were analysed with western blots, apoptosis assays and immunohistochemistry.Key ResultsEarly (7 days) after bleomycin treatment of rats, pulmonary arterial thickening and severe loss of pulmonary arterial endothelium were observed, followed (14 days) by increased right ventricular systolic pressure and right ventricular hypertrophy. Marked down‐regulation of the BMP9/BMPR2/SMAD signalling pathway was markedly down‐regulated in lung tissues from bleomycin‐treated rats (throughout the 7‐ to 35‐day treatment period) and bleomycin‐treated rat PMVECs, along with excessive cell apoptosis and loss of pulmonary arterial endothelium. Treatment with recombinant human bone morphogenetic protein 9 (rhBMP9) attenuated these aspects of bleomycin‐induced pulmonary hypertension, by restoring disrupted BMP9/BMPR2/SMAD signalling.Conclusion and ImplicationsIn bleomycin‐treated rats, early and persisting suppression of the BMP9/BMPR2/SMAD signalling pathway triggered severe loss of pulmonary arterial endothelium and subsequent pulmonary arterial vascular remodelling, contributing to the development of pulmonary hypertension. Therapeutic approaches reinforcing BMP9/BMPR2/SMAD signalling might be ideal strategies for this subtype of pulmonary hypertension.LINKED ARTICLESThis article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc