title: Activation of PI3K/mTOR signaling pathway contributes to induction of vascular endothelial growth factor by hCG in bovine developing luteal cells.
abstract: We recently reported that HIF-1α plays a critical role in the regulation of vascular endothelial growth factor (VEGF) expression in the developing letual cells (LCs) and VEGF-dependent angiogenesis is essential for normal luteal development. Although it is believed that hypoxia is the primary inducer of VEGF, recent reports have also shown that human chorionic gonadotrophin (hCG) up-regulates VEGF expression in developing corpus luteum (CL). Therefore the present study was designed to test the induced effects of hCG on the expression of VEGF and HIF-1α in LCs under normoxic and hypoxic conditions. In addition, we also investigated whether the signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) are involved in hCG-induced VEGF in LCs. A significant increase of VEGF mRNA was found in LCs treated with hCG, which was consistent with the changes of HIF-1α protein, even under hypoxic conditions. However, there was no obvious changes of HIF-1α mRNA in hCG-treated LCs between normoxic and hypoxic conditions, indicating hCG induces VEGF expression by increasing transcription of HIF-1α, while hypoxia mainly increases HIF-1α protein stability. When LCs were pretreated with inhibitors, we found that the PI3K/mTOR signaling pathway is required for HIF-1α and VEGF expression induced by hCG, while the MAPK pathway is not required. Together, these results suggest that activation of IP3K/mTOR signaling pathway contributes to the induction of VEGF and HIF-1α in hCG-treated LCs. To our knowledge this will provide a new insight into the important mechanism of hCG/LH-induced VEGF-dependent angiogenesis in the bovine ovary.
authors.affiliation: Department of Animal Science, College of Animal Science and Technology, Anhui Science and Technology University, Bengbu 233100, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Debing
authors.initials: D
authors.lastname: Yu
authors.forename: Dingzhong
authors.initials: D
authors.lastname: Yin
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000662:veterinary; D002417:Cattle / Q000502:physiology*; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003338:Corpus Luteum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D008184:Luteal Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D006063:Chorionic Gonadotropin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012313:RNA; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A