Hypoxia regulates cell proliferation and steroidogenesis through protein kinase A signaling in bovine corpus luteum.
Hypoxia is an important physiological process which ensures corpus luteum (CL) formation and development, thus playing an important role in steroidogenesis. Recent studies have shown that CL develops in an analogous to tumorigenesis by accumulation of hypoxia-inducible factor-1 alpha subunit (HIF1A) in response to hypoxia. To investigate the relationship among hypoxia, steroidogenesis, and cell proliferation during CL lifespan, histological and steroidogenic analyses of CL were performed at various CL stages in non-pregnant Holstein. Also, the hypoxia-mediated steroidogenesis and cell proliferation were studied in vitro with both primary luteal and luteinized granulosa cells. Our results showed that progesterone (P(4)) concentration increased with the upregulation of steroidogenic protein including steroidogenic acute regulatory protein (STAR) and CYP11A1 (P450scc) in the middle luteal stage. On the other hand, the cell proliferation- or hypoxia-associated proteins were upregulated in the early stage, including the proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor A (VEGFA), HIF1A, and aryl hydrocarbon receptor nuclear translocator (ARNT). In primary culture, phospho-protein kinase A (p-PKA) was downregulated, as were P(4) secretion and steroidogenic proteins both under oxygen-conditioned hypoxia in luteal cells and cobalt chloride-induced hypoxia in luteinized granulosa cells. However, under the treatment of hypoxia, PCNA, which was downregulated in luteal cells, was upregulated together with HIF1A and VEGFA in luteinized granulosa cells. Taken together, present study suggested that hypoxia downregulated steroidogenesis through PKA signaling and that the hypoxia-regulated cell proliferation could be activated during CL formation.
Laboratory of Animal Physiology, Department of Animal Science and Technology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan, ROC.
Yi-Fan
YF
Jiang
Kuan-Hao
KH
Tsui
Peng-Hui
PH
Wang
Cheng-Wei
CW
Lin
Jyun-Yuan
JY
Wang
Meng-Chieh
MC
Hsu
Yi-Chen
YC
Chen
Chih-Hsien
CH
Chiu
D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis; D003338:Corpus Luteum / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D010100:Oxygen / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis; D011374:Progesterone / Q000096:biosynthesis*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000098682:Steroidogenic Acute Regulatory Protein
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D018336:Receptors, Aryl Hydrocarbon; D042461:Vascular Endothelial Growth Factor A; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D002786:Cholesterol Side-Chain Cleavage Enzyme; D017868:Cyclic AMP-Dependent Protein Kinases; D010100:Oxygen