Apelin/APJ signaling promotes hypoxia-induced proliferation of endothelial progenitor cells via phosphoinositide-3 kinase/Akt signaling

Endothelial progenitor cells (EPCs) can adhere to the endothelium at sites of hypoxia/ischemia and participate in the formation of novel vessels through differentiating into endothelial cells (ECs). Apelin is an endogenous ligand for the G protein-coupled receptor APJ, and apelin/APJ signaling has a role in cardiovascular function. The present study aimed to investigate the role of apelin/APJ signaling in the regulation of EPC proliferation under hypoxia. The results showed that hypoxia was able to induce EPC proliferation, accompanied with an upregulation of hypoxia-inducible factor (HIF)-1 alpha as well as apelin/APJ signaling. Further investigation indicated that siRNA-mediated knockdown of apelin or APJ expression attenuated the hypoxia-induced proliferation of EPCs, suggesting that apelin/APJ signaling has an important role in hypoxia-induced EPC proliferation. Moreover, the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway was found to be involved in the apelin/APJ-mediated EPC proliferation under hypoxia. Based on these findings, the present study suggested that hypoxia-induced upregulation of HIF-1 alpha promotes the expression of apelin and APJ, which further activate the downstream PI3K/Akt signaling pathway, a key promoter of EPC proliferation. In conclusion, the present study highlighted the role of apelin/APJ in the regulation of EPC proliferation, and apelin/APJ may therefore serve as a potential target for the prevention of hypoxic ischemic injury.