EFEMP2 mediates pulmonary arterial hypertension via activating the PI3K/Akt pathway

Pulmonary arterial hypertension (PAH) is a severe and progressive pulmonary vascular disorder driven by vascular remodeling, for which current pharmacotherapies remain inadequate. Therefore, the identification of novel therapeutic targets to reverse pulmonary vascular remodeling is urgently needed. Proteomic profiling identified fibulin-like extracellular matrix protein 2 (EFEMP2) as significantly upregulated in the circulation of patients with idiopathic pulmonary arterial hypertension (IPAH), which was further validated by ELISA in an independent cohort. To delineate the cellular landscape of EFEMP2 expression, we re-analyzed a public single-cell RNA sequencing dataset (GSE169471). Pulmonary hypertension (PH) models were established in rats using monocrotaline and in mice using hypoxia, with adeno-associated virus 9 (AAV9)-mediated EFEMP2 knockdown in the mouse model to establish a preventive model. EFEMP2 was silenced in pulmonary artery smooth muscle cells (PASMCs) using small interfering RNA (siRNA), followed by platelet-derived growth factor-BB (PDGF-BB) stimulation. The physical interaction between EFEMP2 and EGFR was examined using co-immunoprecipitation and immunofluorescence colocalization assays. RNA-seq was performed to explore the downstream pathways. EFEMP2 was markedly elevated in patients with IPAH and PH models. Single-cell analysis revealed that EFEMP2 was predominantly enriched and significantly upregulated in the smooth muscle cell cluster of IPAH lungs. In hypoxic mice, EFEMP2 knockdown significantly reduced right ventricular systolic pressure and attenuated vascular remodeling. In vitro, EFEMP2 silencing suppressed PDGF-BB-induced PASMC proliferation and migration, whereas recombinant EFEMP2 protein was sufficient to promote these effects. Mechanistically, EFEMP2 physically interacts with EGFR on the cell membrane and activates the PI3K/Akt signaling pathway, driving PASMC proliferation and migration. EFEMP2 acts as a critical mediator of PAH by interacting with EGFR to activate PI3K/Akt signaling and promote PASMC proliferation and migration, highlighting its potential as a novel therapeutic target for PAH.