DNMT1 deficiency promotes pulmonary vascular remodeling in pulmonary hypertension through epigenetic upregulation of BMP7.

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder marked by pathological vascular remodeling, predominantly driven by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Although bone morphogenetic protein 7 (BMP7) has been implicated in PASMCs dysregulation, the precise upstream mechanisms governing its expression in PH remain elusive. METHODS: In vitro and in vivo models of hypoxia-induced PH were employed. The mRNA and protein levels of the different molecules were quantified using qRT-PCR and Western blot. The role of BMP7 in PASMCs proliferation, cell cycle progression and apoptosis were assessed using Cell Counting Kit-8 (CCK-8) assays, Western blotting, immunofluorescence, and flow cytometry. Moreover, the epigenetic regulatory mechanisms of BMP7 were elucidated using Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and quantitative methylation-specific PCR (qMSP). In vivo functional roles of BMP7 were validated using recombinant protein administration and AAV5-mediated gene knockdown in hypoxic mice, with evaluations of hemodynamics, echocardiography, and vascular remodeling. RESULTS: Hypoxia significantly upregulated BMP7 expression in PASMCs and lung tissues of PH models. Exogenous BMP7 enhanced PASMCs proliferation, accelerated cell cycle progression and suppressed apoptosis. Conversely, BMP7 knockdown attenuated these pro-proliferative and anti-apoptotic responses. Mechanistically, DNMT1 was downregulated under hypoxia, and its genetic or pharmacological inhibition elevated BMP7 expression, whereas DNMT1 overexpression suppressed BMP7. ChIP-qPCR verified DNMT1 binding to the BMP7 promoter CpG island, and qMSP confirmed that DNMT1 loss reduced BMP7 promoter methylation. Consistent with a pathogenic role, BMP7 knockdown alleviated hypoxia-induced right ventricular hypertrophy and vascular remodeling, while BMP7 supplementation exacerbated these phenotypes. CONCLUSIONS: Our study unveils the DNMT1-BMP7 axis as a critical epigenetic pathway in PH. Hypoxia-induced DNMT1 downregulation derepresses BMP7 via promoter hypomethylation, driving PASMCs proliferation and pathological vascular remodeling. Targeting this axis may offer novel therapeutic strategies for PH.