Substance P Promotes Pulmonary Hypertension by Inducing Fibulin-2 Methylation to Regulate β-Catenin

Pulmonary arterial hypertension (PAH) is a fatal disease with limited available treatments and is characterized by pulmonary vascular remodeling. Substance P (SP) may be involved in vascular remodeling in patients with PAH. However, the underlying mechanism is currently unknown. In this study, we found that plasma SP levels were elevated and correlated with pulmonary hemodynamic parameters in PAH patients. SP receptor inhibitors significantly suppressed pulmonary vascular remodeling and improved pulmonary circulation hemodynamics in PAH rats. Multiple omics analyses suggested that downregulation of Fibulin-2 (Fbln2) may play a role in promoting pulmonary vascular remodeling by SP. In addition, the downregulation of Fbln2 expression by SP was further verified by Western blot analysis and immunofluorescence. In vitro experiments showed that SP negatively regulated β-catenin expression by downregulating Fbln2 expression. Moreover, SP promoted the DNA methylation of Fbln2. A methylation inhibitor alleviated SP mediated low expression of Fbln2 and high expression of β-catenin. Overexpression of Fbln2 inhibited the proliferation and migration of pulmonary artery smooth muscle cells induced by SP. These data provide a novel mechanism through which SP promotes the proliferation and migration of PASMCs, leading to pulmonary hypertension and suggesting that Fbln2 is a potential therapeutic target for PAH.