RELA promotes hypoxia-induced angiogenesis in human umbilical vascular endothelial cells via LINC01693/miR-302d/CXCL12 axis

Hypoxia-induced angiogenesis plays a critical role in wound healing, which could be disturbed by multifactors. Upon hypoxia stimulation, CXCL12 and its receptor CXCR4 were significantly upregulated in human umbilical vascular endothelial cells (HUVECs); thus, we attempted to investigate the role and mechanism of CXCL12 in HUVEC angiogenesis under hypoxia. Via downloading and analyzing microarray profiles (GSE76743 and GSE116909), we found that LINC01693 was positively correlated with CXCL12 and upregulated by hypoxia in HUVECs, while miR-302d was downregulated by hypoxia and might target LINC01693 and CXCL12. RELA, a critical transcriptional factor for response to hypoxia, could bind to LINC01693 promoter to activate its transcription, therefore, promoting CXCL12 expression under hypoxia. LINC01693 served as a competing endogenous RNA for miR-302d to counteract miR-302d-mediated CXCL12 suppression via direct targeting. Hypoxia-induced CXCL12 upregulation and angiogenesis in HUVECs could be significantly suppressed by LINC01693 silence while enhanced by miR-302d inhibition; the effect of LINC01693 silence could be partially reversed by miR-302d inhibition. Taken together, RELA promotes the angiogenesis in HUVECs via LINC01693/miR-302d/CXCL12 axis. We provide a novel mechanism and experimental basis of CXCL12 function in hypoxia-induced HUVEC angiogenesis.