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Regulation of angiogenic behaviors by oxytocin receptor through Gli1-indcued transcription of HIF-1α in human umbilical vein endothelial cells

Angiogenesis is a dynamic hypoxia-stimulated process playing a key role in tissue growth and repair under various pathophysiological circumstances. Abnormal angiogenesis contributes to the pathogenesis of many human diseases. Oxytocin receptor is a classical G-protein-coupled receptor expressed on endothelial cells. The present study was aimed to investigate how oxytocin receptor regulated the angiogenic behaviors of human umbilical vein endothelial cells (HUVECs). We found that oxytocin at 0.1μM significantly increased cell proliferation, upregulated the mRNA and protein expression of CD31 and vWF (two important endothelial markers), and enhanced the tuber formation capacity in HUVECs. However, oxytocin receptor inhibitor atosiban at 10μM significantly suppressed these angiogenic properties of HUVECs. Additionally, hypoxia-inducible factor-1α (HIF-1α) inhibitor PX-478 at 20μM also remarkably inhibited the angiogenic properties of HUVECs. We further found that atosiban at 10μM significantly repressed the promoter activity of HIF-1α and reduced the mRNA and protein expression of HIF-1α in HUVECs. Moreover, pharmacological inhibition of HIF-1α by PX-478 at 20μM abolished oxytocin-enhanced angiogenic properties of HUVECs. Finally, transcription factor Gli1 inhibitor GANT-58 at 5μM significantly abolished oxytocin-induced mRNA and protein expression of HIF-1α, while the nuclear abundance of Gli1 was significantly reduced by atosiban at 10μM, but was increased by oxytocin at 0.1μM in HUVECs. GANT-58 at 5μM also significantly abolished oxytocin-enhanced angiogenic properties of HUVECs. Altogether, these discoveries suggested that oxytocin receptor signaling promoted the angiogenic behaviors of HUVECs via Gli1-indcued transcription of HIF-1α. We provided novel molecular insights into endothelial cell-mediated angiogenesis.

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S7612 PX-478 2HCl PX-478 2HCl is an orally active, and selective hypoxia-inducible factor-1α (HIF-1α) inhibitor. PX-478 2HCl induces apoptosis and has anti-tumor activity. Phase 1.

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HIF