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Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
REVIEW

Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

Ryo Nishimura A B and Kiyoshi Okuda A C
+ Author Affiliations
- Author Affiliations

A Laboratory of Reproductive Endocrinology, Graduate School of Natural Science and Technology, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan.

B Present address: Laboratory of Theriogenology, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, 4-101 Koyama-minami, Tottori 680-8550, Japan.

C Corresponding author. Email: kokuda@okayama-u.ac.jp

Reproduction, Fertility and Development 28(10) 1479-1486 https://doi.org/10.1071/RD15010
Submitted: 8 January 2015  Accepted: 13 March 2015   Published: 5 May 2015

Abstract

There is increasing interest in the role of oxygen conditions in the microenvironment of organs because of the discovery of a hypoxia-specific transcription factor, namely hypoxia-inducible factor (HIF) 1. Ovarian function has several phases that change day by day, including ovulation, follicular growth and corpus luteum formation and regression. These phases are regulated by many factors, including pituitary hormones and local hormones, such as steroids, peptides and cytokines, as well as oxygen conditions. Hypoxia strongly induces angiogenesis because transcription of the potent angiogenic factor vascular endothelial growth factor (VEGF) is regulated by HIF1. Follicular development and luteal formation are accompanied by a marked increase in angiogenesis assisted by HIF1–VEGF signalling. Hypoxia is also one of the factors that induces luteolysis by suppressing progesterone synthesis and by promoting apoptosis of luteal cells. The present review focuses on recent studies of hypoxic conditions, as well as HIF1-regulated genes and proteins, in the regulation of ovarian function.

Additional keywords: angiogenesis, apoptosis, corpus luteum, follicular development, luteal formation, luteal regression, steroidogenesis.


References

Acosta, T. J., Yoshizawa, N., Ohtani, M., and Miyamoto, A. (2002). Local changes in blood flow within the early and midcycle corpus luteum after prostaglandin F(2 alpha) injection in the cow. Biol. Reprod. 66, 651–658.
Local changes in blood flow within the early and midcycle corpus luteum after prostaglandin F(2 alpha) injection in the cow.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XhvVeitb0%3D&md5=461e7b4e7176385042640edbd99181c2CAS | 11870071PubMed |

Bacci, M. L., Barazzoni, A. M., Forni, M., and Costerbosa, G. L. (1996). In situ detection of apoptosis in regressing corpus luteum of pregnant sow: evidence of an early presence of DNA fragmentation. Domest. Anim. Endocrinol. 13, 361–372.
In situ detection of apoptosis in regressing corpus luteum of pregnant sow: evidence of an early presence of DNA fragmentation.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK28vjs1yisQ%3D%3D&md5=71ec1466d1a5d0d616378ea69700ef0eCAS | 8839629PubMed |

Basini, G., Bianco, F., Grasselli, F., Tirelli, M., Bussolati, S., and Tamanini, C. (2004). The effects of reduced oxygen tension on swine granulosa cell. Regul. Pept. 120, 69–75.
The effects of reduced oxygen tension on swine granulosa cell.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXks1Wktbg%3D&md5=d44bedc548959767e92aea2ea76d0c86CAS | 15177922PubMed |

Beck, I., Weinmann, R., and Caro, J. (1993). Characterization of hypoxia-responsive enhancer in the human erythropoietin gene shows presence of hypoxia-inducible 120-Kd nuclear DNA-binding protein in erythropoietin-producing and nonproducing cells. Blood 82, 704–711.
| 1:CAS:528:DyaK2cXitVGg&md5=2741fe47af6abbe43da8a0cff8c1b575CAS | 8338939PubMed |

Behrooz, A., and Ismail-Beigi, F. (1997). Dual control of glut1 glucose transporter gene expression by hypoxia and by inhibition of oxidative phosphorylation. J. Biol. Chem. 272, 5555–5562.
Dual control of glut1 glucose transporter gene expression by hypoxia and by inhibition of oxidative phosphorylation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXhslals7o%3D&md5=34fce2bc529678845e6c27655ba414f0CAS | 9038162PubMed |

Boonyaprakob, U., Gadsby, J. E., Hedgpeth, V., Routh, P. A., and Almond, G. W. (2005). Expression and localization of hypoxia inducible factor-1alpha mRNA in the porcine ovary. Can. J. Vet. Res. 69, 215–222.
| 1:CAS:528:DC%2BD2MXpvVWhtro%3D&md5=c3b079eb9631a65bdc725fe42330923cCAS | 16187552PubMed |

Bruick, R. K. (2000). Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc. Natl Acad. Sci. USA 97, 9082–9087.
Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXls12ksrg%3D&md5=63f7c7cfc312bb522a44fc7c8ddb9697CAS | 10922063PubMed |

Bruick, R. K. (2003). Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 17, 2614–2623.
Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXovVaht70%3D&md5=7b1d9db52129ac0a04f166ef3d225399CAS | 14597660PubMed |

Carroll, V. A., and Ashcroft, M. (2005). Targeting the molecular basis for tumour hypoxia. Expert Rev. Mol. Med. 7, 1–16.
Targeting the molecular basis for tumour hypoxia.Crossref | GoogleScholarGoogle Scholar | 15831177PubMed |

Chen, L., Endler, A., and Shibasaki, F. (2009). Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp. Mol. Med. 41, 849–857.
Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXksFaktw%3D%3D&md5=2b498ac0e4b2fc2e449231ad5fd33c6dCAS | 19942820PubMed |

Cockman, M. E., Masson, N., Mole, D. R., Jaakkola, P., Chang, G. W., Clifford, S. C., Maher, E. R., Pugh, C. W., Ratcliffe, P. J., and Maxwell, P. H. (2000). Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem. 275, 25 733–25 741.
Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXmtVeht7o%3D&md5=6b01f89c22a9a5047d67ab0073aba868CAS |

Coulet, F., Nadaud, S., Agrapart, M., and Soubrier, F. (2003). Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J. Biol. Chem. 278, 46 230–46 240.
Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXovFKlt7k%3D&md5=bbe284fdff0daac39e89f62c44a4ced4CAS |

de Castro e Paula, L. A., Andrzejewski, J., Julian, D., Spicer, L. J., and Hansen, P. J. (2008). Oxygen and steroid concentrations in preovulatory follicles of lactating dairy cows exposed to acute heat stress. Theriogenology 69, 805–813.
Oxygen and steroid concentrations in preovulatory follicles of lactating dairy cows exposed to acute heat stress.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXktFClsbs%3D&md5=bab0ef11919e802f0a24326cdf9433f2CAS | 18243293PubMed |

Duncan, W. C., van den Driesche, S., and Fraser, H. M. (2008). Inhibition of vascular endothelial growth factor in the primate ovary up-regulates hypoxia-inducible factor-1alpha in the follicle and corpus luteum. Endocrinology 149, 3313–3320.
Inhibition of vascular endothelial growth factor in the primate ovary up-regulates hypoxia-inducible factor-1alpha in the follicle and corpus luteum.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXot1amurY%3D&md5=7fbf4bd1ea75d92beb604cf8cec3d208CAS | 18388198PubMed |

Dunwoodie, S. L. (2009). The role of hypoxia in development of the mammalian embryo. Dev. Cell 17, 755–773.
The role of hypoxia in development of the mammalian embryo.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXht1Cjsb8%3D&md5=ea86e5154f20ea91e22c3725ba9ffe7aCAS | 20059947PubMed |

Fadhillah, , Yoshioka, S., Nishimura, R., and Okuda, K. (2014). Hypoxia promotes progesterone synthesis during luteinization in bovine granulosa cells. J. Reprod. Dev. 60, 194–201.
Hypoxia promotes progesterone synthesis during luteinization in bovine granulosa cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhtlOmsbjK&md5=351642b5c81afdf5bde6d9225d3fb948CAS | 24583842PubMed |

Ferrara, N., and Henzel, W. J. (1989). Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851–858.
Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1MXkslWhtbY%3D&md5=c3bef598d8716bca68d0998932dcf0f3CAS | 2735925PubMed |

Ferrara, N., Gerber, H. P., and LeCouter, J. (2003). The biology of VEGF and its receptors. Nat. Med. 9, 669–676.
The biology of VEGF and its receptors.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXktFOnur4%3D&md5=bbb1836653413f8cc9a1ace2794511bbCAS | 12778165PubMed |

Firth, J. D., Ebert, B. L., Pugh, C. W., and Ratcliffe, P. J. (1994). Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer. Proc. Natl Acad. Sci. USA 91, 6496–6500.
Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXlt1Krsbw%3D&md5=56957e0e970f662f01f2e3c28ed9b3feCAS | 8022811PubMed |

Fischer, B., Kunzel, W., Kleinstein, J., and Gips, H. (1992). Oxygen tension in follicular fluid falls with follicle maturation. Eur. J. Obstet. Gynecol. Reprod. Biol. 43, 39–43.
Oxygen tension in follicular fluid falls with follicle maturation.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK387ks1Klsw%3D%3D&md5=fb42281e111636295b50ca5351780bccCAS | 1737607PubMed |

Ford, S. P., and Chenault, J. R. (1981). Blood flow to the corpus luteum-bearing ovary and ipsilateral uterine horn of cows during the oestrous cycle and early pregnancy. J. Reprod. Fertil. 62, 555–562.
Blood flow to the corpus luteum-bearing ovary and ipsilateral uterine horn of cows during the oestrous cycle and early pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL3MXksF2hs7o%3D&md5=89977c695b8e4bcb745c36a9af3869a1CAS | 7252931PubMed |

Forsythe, J. A., Jiang, B. H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., and Semenza, G. L. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16, 4604–4613.
| 1:CAS:528:DyaK28XltFKjsrc%3D&md5=894ee75b3b3f398955e2a15510ef9332CAS | 8756616PubMed |

Frota, I. M., Leitao, C. C., Costa, J. J., Brito, I. R., van den Hurk, R., and Silva, J. R. (2011). Stability of housekeeping genes and expression of locally produced growth factors and hormone receptors in goat preantral follicles. Zygote 19, 71–83.
Stability of housekeeping genes and expression of locally produced growth factors and hormone receptors in goat preantral follicles.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXjtVSnsw%3D%3D&md5=29c19058dd9fe6c52ed3101538629520CAS | 20587134PubMed |

Gleadle, J. M., and Ratcliffe, P. J. (1997). Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood 89, 503–509.
| 1:CAS:528:DyaK2sXlt1WjtA%3D%3D&md5=9ae96a174335aaf1dbd71995e88c8a0eCAS | 9002952PubMed |

Grazul-Bilska, A. T., Redmer, D. A., Killilea, S. D., Zheng, J., and Reynolds, L. P. (1993). Initial characterization of endothelial mitogens produced by bovine corpora lutea from the estrous cycle. Biochem. Cell Biol. 71, 270–277.
Initial characterization of endothelial mitogens produced by bovine corpora lutea from the estrous cycle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXntVQ%3D&md5=05fb755e277ea9a1202c894f2c17ad13CAS | 7506042PubMed |

Hellwig-Bürgel, T., Stiehl, D. P., Wagner, A. E., Metzen, E., and Jelkmann, W. (2005). Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J. Interferon Cytokine Res. 25, 297–310.
Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions.Crossref | GoogleScholarGoogle Scholar | 15957953PubMed |

Hosseini, A., Sauerwein, H., and Mielenz, M. (2010). Putative reference genes for gene expression studies in propionate and beta-hydroxybutyrate treated bovine adipose tissue explants. J. Anim. Physiol. Anim. Nutr. (Berl.) 94, e178–e184.
Putative reference genes for gene expression studies in propionate and beta-hydroxybutyrate treated bovine adipose tissue explants.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlSgtLvN&md5=62fc7fce17e4cd0d01d31ed44e251dc9CAS | 20579188PubMed |

Huang, L. E., Gu, J., Schau, M., and Bunn, H. F. (1998). Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl Acad. Sci. USA 95, 7987–7992.
Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXks1SlsrY%3D&md5=6819a4f912b800036d8e7969f8a95ed5CAS | 9653127PubMed |

Ietta, F., Wu, Y., Winter, J., Xu, J., Wang, J., Post, M., and Caniggia, I. (2006). Dynamic HIF1A regulation during human placental development. Biol. Reprod. 75, 112–121.
Dynamic HIF1A regulation during human placental development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xmtlyisbo%3D&md5=5d4605568de783933b3ef17a1ad9b4aeCAS | 16611863PubMed |

Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., and Kaelin, W. G. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468.
HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjtVentbw%3D&md5=09aeea7f54598eebeb8bef6dd006dcbfCAS | 11292862PubMed |

Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M. I., Gielbert, J., Gaskell, S. J., von Kriegsheim, A., Hebestreit, H. F., Mukherji, M., Schofield, C. J., Maxwell, P. H., Pugh, C. W., and Ratcliffe, P. J. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472.
Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjtVentb0%3D&md5=2153b94704a5845590890ca1daf1aa5aCAS | 11292861PubMed |

Jelkmann, W. (2004). Molecular biology of erythropoietin. Intern. Med. 43, 649–659.
Molecular biology of erythropoietin.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhtVahsLbO&md5=48eacec28fff5ebedeea3c02f0f56c05CAS | 15468961PubMed |

Jiang, B. H., Semenza, G. L., Bauer, C., and Marti, H. H. (1996). Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol. 271, C1172–C1180.
| 1:CAS:528:DyaK28XmsF2nurw%3D&md5=922fd6eebac6f7137d82feab7a7d97c7CAS | 8897823PubMed |

Juengel, J. L., Garverick, H. A., Johnson, A. L., Youngquist, R. S., and Smith, M. F. (1993). Apoptosis during luteal regression in cattle. Endocrinology 132, 249–254.
| 1:CAS:528:DyaK3sXhsVSmsbs%3D&md5=5028020e71dc296fda947c2e05815a65CAS | 8419126PubMed |

Kallio, P. J., Wilson, W. J., O’Brien, S., Makino, Y., and Poellinger, L. (1999). Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J. Biol. Chem. 274, 6519–6525.
Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXhs1Cjsr8%3D&md5=23851118649abfee95556f053dd04b70CAS | 10037745PubMed |

Kamat, B. R., Brown, L. F., Manseau, E. J., Senger, D. R., and Dvorak, H. F. (1995). Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am. J. Pathol. 146, 157–165.
| 1:CAS:528:DyaK2MXjs1yju7w%3D&md5=087d77c373ea2d45327350a13b4be95dCAS | 7531945PubMed |

Kamura, T., Sato, S., Iwai, K., Czyzyk-Krzeska, M., Conaway, R. C., and Conaway, J. W. (2000). Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc. Natl Acad. Sci. USA 97, 10 430–10 435.
Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXms1Crsb4%3D&md5=08ab3d9afdcdb268b1c0c42c6921f87fCAS |

Kimura, H., Weisz, A., Ogura, T., Hitomi, Y., Kurashima, Y., Hashimoto, K., D’Acquisto, F., Makuuchi, M., and Esumi, H. (2001). Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J. Biol. Chem. 276, 2292–2298.
Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXotVCktw%3D%3D&md5=12f81e3758aeeffce44e98be96efacffCAS | 11056166PubMed |

Lee, P. J., Jiang, B. H., Chin, B. Y., Iyer, N. V., Alam, J., Semenza, G. L., and Choi, A. M. (1997). Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J. Biol. Chem. 272, 5375–5381.
Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXhslamurk%3D&md5=44b8ce8dcd482dcb15965a90f09aea6fCAS | 9038135PubMed |

Lee, J. W., Bae, S. H., Jeong, J. W., Kim, S. H., and Kim, K. W. (2004). Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp. Mol. Med. 36, 1–12.
Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions.Crossref | GoogleScholarGoogle Scholar | 15031665PubMed |

Magness, R. R., Christenson, R. K., and Ford, S. P. (1983). Ovarian blood flow throughout the estrous cycle and early pregnancy in sows. Biol. Reprod. 28, 1090–1096.
Ovarian blood flow throughout the estrous cycle and early pregnancy in sows.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL3sXksVyjtLY%3D&md5=f05836eda5ed717cf1af0f81d35c09dbCAS | 6871309PubMed |

Matsuda, F., Inoue, N., Manabe, N., and Ohkura, S. (2012). Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells. J. Reprod. Dev. 58, 44–50.
Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XlvVOntr0%3D&md5=4a8b1b661cb295c8785021bd845242c5CAS | 22450284PubMed |

Maxwell, P. H., Wiesener, M. S., Chang, G. W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., and Ratcliffe, P. J. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275.
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXjsFyqt74%3D&md5=014071430518f30a0908c5b465b278d4CAS | 10353251PubMed |

McCracken, J. A., Custer, E. E., and Lamsa, J. C. (1999). Luteolysis: a neuroendocrine-mediated event. Physiol. Rev. 79, 263–323.
| 1:CAS:528:DyaK1MXivFektLg%3D&md5=4618652c1671c72ca99657d74825cf2eCAS | 10221982PubMed |

Meidan, R., Klipper, E., Zalman, Y., and Yalu, R. (2013). The role of hypoxia-induced genes in ovarian angiogenesis. Reprod. Fertil. Dev. 25, 343–350.
The role of hypoxia-induced genes in ovarian angiogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhslartrk%3D&md5=0be57d3f745e01dc360746c804d68223CAS | 22950963PubMed |

Nett, T. M., McClellan, M. C., and Niswender, G. D. (1976). Effects of prostaglandins on the ovine corpus luteum: blood flow, secretion of progesterone and morphology. Biol. Reprod. 15, 66–78.
Effects of prostaglandins on the ovine corpus luteum: blood flow, secretion of progesterone and morphology.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE2sXltVM%3D&md5=bd9e4608dfcca5d3eaa8ef6d7f490222CAS | 986194PubMed |

Nishimura, R., and Okuda, K. (2010). Hypoxia is important for establishing vascularization during corpus luteum formation in cattle. J. Reprod. Dev. 56, 110–116.
Hypoxia is important for establishing vascularization during corpus luteum formation in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXksVymtr0%3D&md5=d955ee3075fc2a6329322b379b9c917aCAS | 19881217PubMed |

Nishimura, R., Sakumoto, R., Tatsukawa, Y., Acosta, T. J., and Okuda, K. (2006). Oxygen concentration is an important factor for modulating progesterone synthesis in bovine corpus luteum. Endocrinology 147, 4273–4280.
Oxygen concentration is an important factor for modulating progesterone synthesis in bovine corpus luteum.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xpt1SjtbY%3D&md5=badb21be8a1e4b0e9f68807d8779a725CAS | 16740971PubMed |

Nishimura, R., Komiyama, J., Tasaki, Y., Acosta, T. J., and Okuda, K. (2008). Hypoxia promotes luteal cell death in bovine corpus luteum. Biol. Reprod. 78, 529–536.
Hypoxia promotes luteal cell death in bovine corpus luteum.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXisFSlurc%3D&md5=529e21740979b0527ffd3e002cfffbfcCAS | 18046014PubMed |

Niswender, G. D., Reimers, T. J., Diekman, M. A., and Nett, T. M. (1976). Blood flow: a mediator of ovarian function. Biol. Reprod. 14, 64–81.
Blood flow: a mediator of ovarian function.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE28XkslaktLY%3D&md5=7a96340c6330fd282445695ca5e9060bCAS | 769853PubMed |

Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T. Y., Huang, L. E., Pavletich, N., Chau, V., and Kaelin, W. G. (2000). Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat. Cell Biol. 2, 423–427.
Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXkvFCqtrk%3D&md5=75e7fdd692285afe84ec0c826fe5f953CAS | 10878807PubMed |

Piret, J. P., Mottet, D., Raes, M., and Michiels, C. (2002). Is HIF-1alpha a pro- or an anti-apoptotic protein? Biochem. Pharmacol. 64, 889–892.
Is HIF-1alpha a pro- or an anti-apoptotic protein?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xms1yms7w%3D&md5=228e5a98ae061cf132591032a8e3d313CAS | 12213583PubMed |

Ravindranath, N., Little-Ihrig, L., Phillips, H. S., Ferrara, N., and Zeleznik, A. J. (1992). Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology 131, 254–260.
| 1:CAS:528:DyaK38XkvVCiu7k%3D&md5=ddd20709dc3e8e8a1556edd128a2522eCAS | 1612003PubMed |

Redding, G. P., Bronlund, J. E., and Hart, A. L. (2008). Theoretical investigation into the dissolved oxygen levels in follicular fluid of the developing human follicle using mathematical modelling. Reprod. Fertil. Dev. 20, 408–417.
Theoretical investigation into the dissolved oxygen levels in follicular fluid of the developing human follicle using mathematical modelling.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjtVKksL0%3D&md5=bc172bc90bc8e54f2b1ebf89606c7057CAS | 18402761PubMed |

Redmer, D. A., and Reynolds, L. P. (1996). Angiogenesis in the ovary. Rev. Reprod. 1, 182–192.
Angiogenesis in the ovary.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK28XmtFWqurg%3D&md5=c48766f52242a81d0584e40497cab861CAS | 9414456PubMed |

Reynolds, L. P., Killilea, S. D., and Redmer, D. A. (1992). Angiogenesis in the female reproductive system. FASEB J. 6, 886–892.
| 1:STN:280:DyaK387lsFCrsw%3D%3D&md5=b6bd901ae10ed89f83b52eaec68b5907CAS | 1371260PubMed |

Reynolds, L. P., Grazul-Bilska, A. T., Killilea, S. D., and Redmer, D. A. (1994). Mitogenic factors of corpora lutea. Prog. Growth Factor Res. 5, 159–175.
Mitogenic factors of corpora lutea.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXksFSitL8%3D&md5=260f892132b1ac152c789a2fb2ac0fb4CAS | 7919222PubMed |

Reynolds, L. P., Grazul-Bilska, A. T., and Redmer, D. A. (2000). Angiogenesis in the corpus luteum. Endocrine 12, 1–9.
Angiogenesis in the corpus luteum.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXjtlKrurY%3D&md5=3d8db2bd9725902fa765052a63953157CAS | 10855683PubMed |

Rueda, B. R., Wegner, J. A., Marion, S. L., Wahlen, D. D., and Hoyer, P. B. (1995). Internucleosomal DNA fragmentation in ovine luteal tissue associated with luteolysis: in vivo and in vitro analyses. Biol. Reprod. 52, 305–312.
Internucleosomal DNA fragmentation in ovine luteal tissue associated with luteolysis: in vivo and in vitro analyses.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXjt12lu7k%3D&md5=a350437a32bd6388f827e9d614471351CAS | 7711200PubMed |

Rueda, B. R., Tilly, K. I., Botros, I. W., Jolly, P. D., Hansen, T. R., Hoyer, P. B., and Tilly, J. L. (1997). Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. Biol. Reprod. 56, 186–193.
Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXis1Ohtw%3D%3D&md5=0db544e8378297f319f6698a9cb24583CAS | 9002648PubMed |

Salceda, S., and Caro, J. (1997). Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem. 272, 22 642–22 647.
Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXlvFGitLk%3D&md5=681b37530d902d9892224336d484c608CAS |

Sawyer, H. R., Niswender, K. D., Braden, T. D., and Niswender, G. D. (1990). Nuclear changes in ovine luteal cells in response to PGF2alpha. Domest. Anim. Endocrinol. 7, 229–237.
Nuclear changes in ovine luteal cells in response to PGF2alpha.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3cXltV2rtbs%3D&md5=e6b4d4191c4766dd8036daff13f76a7bCAS | 2369821PubMed |

Semenza, G. L., and Wang, G. L. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12, 5447–5454.
| 1:CAS:528:DyaK3sXltFShsr0%3D&md5=107761d021d785ff27771be4d0431438CAS | 1448077PubMed |

Semenza, G. L., Jiang, B. H., Leung, S. W., Passantino, R., Concordet, J. P., Maire, P., and Giallongo, A. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32 529–32 537.
Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXmsFOl&md5=29299f172c145dcebc38600468fbd440CAS |

Tanimoto, K., Makino, Y., Pereira, T., and Poellinger, L. (2000). Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19, 4298–4309.
Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXnt1yrtrw%3D&md5=fb324bec278b14b8eb9a206616ffbea7CAS | 10944113PubMed |

Tscheudschilsuren, G., Aust, G., Nieber, K., Schilling, N., and Spanel-Borowski, K. (2002). Microvascular endothelial cells differ in basal and hypoxia-regulated expression of angiogenic factors and their receptors. Microvasc. Res. 63, 243–251.
Microvascular endothelial cells differ in basal and hypoxia-regulated expression of angiogenic factors and their receptors.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XjtVentbs%3D&md5=f5b447aa5750d583d2f95cd58da9dba8CAS | 11969301PubMed |

van den Driesche, S., Myers, M., Gay, E., Thong, K. J., and Duncan, W. C. (2008). HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum. Mol. Hum. Reprod. 14, 455–464.
HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtVSjsr7M&md5=7c3bee89ed8d2dcb0434307e5bd04d49CAS | 18591213PubMed |

Varshney, N., Mohanty, A. K., Kumar, S., Kaushik, J. K., Dang, A. K., Mukesh, M., Mishra, B. P., Kataria, R., Kimothi, S. P., Mukhopadhyay, T. K., Malakar, D., Prakash, B. S., Grover, S., and Batish, V. K. (2012). Selection of suitable reference genes for quantitative gene expression studies in milk somatic cells of lactating cows (Bos indicus). J. Dairy Sci. 95, 2935–2945.
Selection of suitable reference genes for quantitative gene expression studies in milk somatic cells of lactating cows (Bos indicus).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xntlyqsbw%3D&md5=8396fff026c1dbca66e277ace63cf03dCAS | 22612931PubMed |

Wang, G. L., and Semenza, G. L. (1995). Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237.
Purification and characterization of hypoxia-inducible factor 1.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXjtFOktr4%3D&md5=124b80677af5398d5020ef4633b1de7dCAS | 7836384PubMed |

Wenger, R. H. (2002). Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 16, 1151–1162.
Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XlslWrs78%3D&md5=df35936027e0c743cf7abb3a0fdbac8bCAS | 12153983PubMed |

Wiesener, M. S., and Maxwell, P. H. (2003). HIF and oxygen sensing; as important to life as the air we breathe? Ann. Med. 35, 183–190.
HIF and oxygen sensing; as important to life as the air we breathe?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXlt1Crt7c%3D&md5=321758a4fb8625eb6bf2e50385485323CAS | 12822740PubMed |

Wise, T. H., Caton, D., Thatcher, W. W., Barron, D. H., and Fields, M. J. (1982). Ovarian function during the estrous cycle of the cow: ovarian blood flow and progesterone release rate. J. Anim. Sci. 55, 627–637.
| 1:CAS:528:DyaL38XlsFKkt7Y%3D&md5=de86ef2598e3e85a6717ee7b281834f8CAS | 6813305PubMed |

Wisnieski, F., Calcagno, D. Q., Leal, M. F., dos Santos, L. C., Gigek Cde, O., Chen, E. S., Pontes, T. B., Assumpcao, P. P., de Assumpcao, M. B., Demachki, S., Burbano, R. R., and Smith Mde, A. (2013). Reference genes for quantitative RT-PCR data in gastric tissues and cell lines. World J. Gastroenterol. 19, 7121–7128.
Reference genes for quantitative RT-PCR data in gastric tissues and cell lines.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXltlKjs7c%3D&md5=9c0cf6aae39244328bc13643a9213511CAS | 24222956PubMed |

Zhang, Z., Yu, D., Yin, D., and Wang, Z. (2011). Activation of PI3K/mTOR signaling pathway contributes to induction of vascular endothelial growth factor by hCG in bovine developing luteal cells. Anim. Reprod. Sci. 125, 42–48.
Activation of PI3K/mTOR signaling pathway contributes to induction of vascular endothelial growth factor by hCG in bovine developing luteal cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXnsVyrur8%3D&md5=afd494c916a9d87b37730d3f5c7a7605CAS | 21477953PubMed |