Endothelial progenitor cell-derived exosomes inhibit pulmonary artery smooth muscle cell in vitro proliferation and resistance to apoptosis by modulating the Mitofusin-2 and Ras-Raf-ERK1/2 signaling pathway

Pulmonary arterial hypertension (PAH) mainly occurs as a result of abnormal proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Endothelial progenitor cell (EPC)-derived exosomes (Exos) (EPC-Exos) relieve PAH. However, there is still insufficient knowledge of whether EPC-Exos contribute to the pathological process of PAH, especially for PASMC repair. This study aimed to determine the effects of EPC-Exos on the proliferation, migration, and apoptosis of PASMCs and explore the possible underlying molecular mechanisms through bioinformatics analysis and in vitro testing. Bioinformatics analysis showed that the Ras signaling pathway and Exos were crucial in PAH. The PAH differential microRNAs (miRNAs) and miRNAs identified in EPC-Exos were intersected to obtain miR-21-5p. A target gene prediction program predicted mitofusin-2 (Mfn2) as a potential target of miR-21-5p. Cellular experiments demonstrated that EPC-Exos attenuated the viability, proliferation, migration, and apoptosis resistance of PASMCs under hypoxia. Mechanistically, EPC-Exos significantly upregulated Mfn2 expression and attenuated Ras-Raf-ERK1/2 signaling pathway activity. In conclusion, EPC-Exos suppress cell viability, proliferation, and migration and promote apoptosis in PASMCs under hypoxic conditions. It is possible to transport miR-21-5p to improve the expression of Mfn2 and inhibit the Ras-Raf-ERK1/2 signaling pathway directly or by targeting the expression of Mfn2. EPC-Exos are a potential therapeutic candidate for the treatment of PAH.