Exosomes derived from HIF-1α modified adipose mesenchymal stem cell- ameliorates pulmonary vascular remodeling via upregulating FOXO1 in mice with pulmonary hypertension

Abstract

Abstract Increasing evidence suggests that adipose mesenchymal stem cells (ADSCs) execute their paracrine effects via the secretion of exosomes, especially under hypoxic conditions. HIF-1α played a critical role in regulating the cellular response to hypoxia and promoting tissue repair through various mechanisms. In present study, we want to assess whether ADSCs derived extracellular vesicles (ADSCs-EVs) could extenuate hypoxia-induced pulmonary vascular remodeling and the role of exosomes derived from HIF-1α modified (Exos-HIF-1α) in endothelial cell (EC) function. Exosomes were isolated from cell culture supernatants and characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Hypoxia-induced pulmonary arterial hypertension (PAH) was attenuated in mice treated with Exos-HIF-1α. Exos-HIF-1α showed a protective role in hypoxia induction led to HPMECs injury and induced autophagy, which were reversed by 3-MA treatment (an autophagy inhibitor). Bioinformatic analyses indicated that FOXO signal pathway and FOXO1 were involved in endothelial dysfunction. Moreover, deletion of FOXO1 or pharmacological inhibition of FOXO1 reduced the effects of Exos-HIF-1α under hypoxia in vitro. In addition, FOXO1 overexpression showed the similar protective impacts on HPMECs injury and autophagy upon hypoxia. Our findings indicated that FOXO1 contributed a crucial role in Exos-HIF-1α in maintaining endothelial function and pulmonary artery remodeling in PAH.