Dysregulation of BMP9/BMPR2/SMAD Signaling Pathway Contributes to the Bleomycin-induced Pulmonary Fibrosis and Pulmonary Hypertension in a Rat Model.

RATIONALE Pulmonary hypertension (PH) related to pulmonary fibrosis (PF) belongs to the WHO Group III, one of the most common subgroups which lacks effective treatment options. In this study, we aim to uncover the underlying mechanism of action, especially the BMP9/BMPR2/SMAD signaling pathway in this subtype of PH. METHODS Male Sprague Dawley rats were used to establish a bleomycin (BLM)-induced PF and PH animal model, and primarily cultured rat pulmonary microvascular endothelial cells (PMVECs) were applied as the cell model. RESULTS Typical PH characteristics were observed at early stage after BLM treatment. First, significantly increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) occurred after 14-days of BLM treatment, while the excessive pulmonary arterial (PA) thickening and severe loss of PA endothelium were observed as early as 7-days after BLM treatment. Then, markedly downregulation of the BMP9/BMPR2/SMAD signaling pathway were determined in both the lung tissues from BLM-treated rats (throughout the 7- to 35-days treatment period) and BLM-treated rat PMVECs, in correlation with the aggravated cell apoptosis and loss of PA endothelium. Notably, treatment of recombinant human bone morphogenetic protein 9 (rhBMP9) significantly attenuated the BLM-induced PH characteristics by restoring the disrupted BMP9/BMPR2/SMAD signaling pathway. CONCLUSION In BLM-treated rats, an early-onset and persistent suppression of the BMP9/BMPR2/SMAD signaling pathway might be a trigger to induce the severe loss of PA endothelium and subsequent PA vascular remodeling, contributing to the development of PH. Therapeutic approaches reinforcing the BMP9/BMPR2/SMAD signaling might be ideal strategies for this subtype of PH.