{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:40:52Z","timestamp":1790019652748,"version":"4.0.1"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2015CB352006"],"award-info":[{"award-number":["2015CB352006"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Owing to the avascular structure of the ovarian follicle, proliferation of granulosa cells (GCs) and development of follicles occur under hypoxia, which is obviously different from the cell survival requirements of most mammalian cells. We hypothesized that autophagy may exert an inhibitory effect on GC apoptosis. To decipher the underlying mechanism, we constructed a rat follicular development model using pregnant mare serum gonadotropin and a cell culture experiment in hypoxic conditions (3% O<jats:sub>2<\/jats:sub>). The present results showed that the autophagy level was obviously increased and was accompanied by the concomitant elevation of hypoxia inducible factor (HIF)-1\u03b1 and BNIP3 (Bcl-2\/adenovirus E1B 19kDa-interacting protein 3) in GCs during follicular development. The levels of Bax (Bcl2-associated X) and Bcl-2 (B-cell lymphoma-2) were increased, while the activation of caspase-3 exhibited no obvious changes during follicular development. However, inhibition of HIF-1\u03b1 attenuated the increase in Bcl-2 and promoted the increase in Bax and cleaved caspase-3. Furthermore, we observed the downregulation of BNIP3 and the decrease in autophagy after treatment with a specific HIF-1\u03b1 activity inhibitor (echinomycin), indicating that HIF-1\u03b1\/BNIP3 was involved in autophagy regulation in GCs <jats:italic>in vivo<\/jats:italic>. In an <jats:italic>in vitro<\/jats:italic> study, we also found that hypoxia did not obviously promote GC apoptosis, while it significantly enhanced the activation of HIF-1\u03b1\/BNIP3 and the induction of autophagy. Expectedly, this effect could be reversed by 3-methyladenine (3-MA) treatment. Taken together, these findings demonstrated that hypoxia drives the activation of HIF-1\u03b1\/BNIP3 signaling, which induces an increase in autophagy, protecting GC from apoptosis during follicular development.<\/jats:p>","DOI":"10.3389\/fcell.2021.631016","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T05:37:02Z","timestamp":1611293822000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["HIF-1\u03b1 Protects Granulosa Cells From Hypoxia-Induced Apoptosis During Follicular Development by Inducing Autophagy"],"prefix":"10.3389","volume":"9","author":[{"given":"Zonghao","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renfeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congjian","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengping","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baorong","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengchao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.4161\/auto.5278","article-title":"Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3.","volume":"4","author":"Azad","year":"2008","journal-title":"Autophagy"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01066","article-title":"Low oxygen levels induce early luteinization associated changes in bovine Granulosa cells.","volume":"9","author":"Baddela","year":"2018","journal-title":"Front. Physiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s11259-005-0031-3","article-title":"Angiogenic activity of swine granulosa cells: effects of hypoxia and the role of VEGF.","volume":"29","author":"Bianco","year":"2005","journal-title":"Vet. Res. Commun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/s1357-2725(98)00006-5","article-title":"Bax. The pro-apoptotic Bcl-2 family member, Bax.","volume":"30","author":"Brady","year":"1998","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"E566","DOI":"10.1152\/ajpendo.00432.2012","article-title":"FSH induces the development of circadian clockwork in rat granulosa cells via a gap junction protein Cx43-dependent pathway.","volume":"304","author":"Chen","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity.","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1016\/j.fertnstert.2010.06.006","article-title":"Induction of apoptotic cell death via accumulation of autophagosomes in rat granulosa cells.","volume":"95","author":"Choi","year":"2011","journal-title":"Fertil. Steril."},{"key":"B8","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1530\/REP-13-0386","article-title":"AKT is involved in granulosa cell autophagy regulation via mTOR signaling during rat follicular development and Atresia.","volume":"147","author":"Choi","year":"2013","journal-title":"Reproduction"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2532","DOI":"10.1016\/j.fertnstert.2009.11.021","article-title":"The role of autophagy in follicular development and atresia in rat granulosa cells.","volume":"93","author":"Choi","year":"2010","journal-title":"Fertil. Steril."},{"key":"B10","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/0028-2243(92)90241-p","article-title":"Oxygen tension in follicular fluid falls with follicle maturation.","volume":"43","author":"Fischer","year":"1992","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.redox.2017.02.012","article-title":"Mitochondrial composition and function under the control of hypoxia.","volume":"12","author":"Fuhrmann","year":"2017","journal-title":"Redox Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1016\/j.cell.2014.11.006","article-title":"Metabolic control of autophagy.","volume":"159","author":"Galluzzi","year":"2014","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1176-7","article-title":"Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a\/Bad\/Bax axis.","volume":"9","author":"Ge","year":"2018","journal-title":"Cell Death Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3392","DOI":"10.1210\/en.2008-0948","article-title":"Signaling by hypoxia-inducible factors is critical for ovulation in mice.","volume":"150","author":"Kim","year":"2009","journal-title":"Endocrinology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/584758","article-title":"Hypoxia inducible factor pathway and physiological adaptation: a cell survival pathway?","volume":"2015","author":"Kumar","year":"2015","journal-title":"Medi. Inflamm."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3631","DOI":"10.1096\/fj.201901808RRR","article-title":"FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1\u03b1-PINK1-Parkin pathway.","volume":"34","author":"Li","year":"2020","journal-title":"FASEB J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1056\/NEJMra2022774","article-title":"Autophagy in human diseases.","volume":"383","author":"Mizushima","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1071\/rd07190","article-title":"Theoretical investigation into the dissolved oxygen levels in follicular fluid of the developing human follicle using mathematical modelling.","volume":"20","author":"Redding","year":"2008","journal-title":"Reprod. Fertil. Dev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1093\/humrep\/13.4.953","article-title":"Cyclic changes of vasculature and vascular phenotypes in normal human ovaries.","volume":"13","author":"Suzuki","year":"1998","journal-title":"Hum. Reprod."},{"key":"B20","first-page":"11384","article-title":"Accumulated autophagosomes and excessive apoptosis during the luteal development of pregnant rats.","volume":"10","author":"Tang","year":"","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5981","DOI":"10.3892\/etm.2017.5328","article-title":"Effects of dimethyl carbonate-induced autophagic activation on follicular development in the mouse ovary.","volume":"14","author":"Tang","year":"","journal-title":"Exp. Ther. Med."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010071","article-title":"Autophagy attenuation hampers progesterone synthesis during the development of pregnant corpus Luteum.","volume":"9","author":"Tang","year":"2019","journal-title":"Cells"},{"key":"B23","doi-asserted-by":"publisher","first-page":"8164","DOI":"10.3892\/mmr.2017.7678","article-title":"Defective insulin signaling and the protective effects of dimethyldiguanide during follicular development in the ovaries of polycystic ovary syndrome.","volume":"16","author":"Wang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s10735-015-9609-4","article-title":"Expression and clinical significance of the HIF-1a\/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome.","volume":"46","author":"Wang","year":"2015","journal-title":"J. Mol. Histol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"615","DOI":"10.3858\/emm.2012.44.10.070","article-title":"Effects of echinomycin on endothelin-2 expression and ovulation in immature rats primed with gonadotropins.","volume":"44","author":"Wang","year":"2012","journal-title":"Exp. Mol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3894","DOI":"10.3892\/mmr.2016.5671","article-title":"Effect of high-fat diet-induced obesity on the Akt\/FoxO\/Smad signaling pathway and the follicular development of the mouse ovary.","volume":"14","author":"Wu","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.bbrc.2015.09.096","article-title":"High fat diet triggers cell cycle arrest and excessive apoptosis of granulosa cells during the follicular development.","volume":"466","author":"Wu","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1262\/jrd.2012-089","article-title":"Regulatory effect of hypoxia-inducible factor-1a on hCG-stimulated endothelin-2 expression in granulosa cells from the PMSG-treated rat ovary.","volume":"58","author":"Zhang","year":"2012","journal-title":"J. Reprod. Dev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/cbin.11090","article-title":"Activation of NF-\u03baB signaling pathway during HCG-induced VEGF expression in luteal cells.","volume":"43","author":"Zhang","year":"","journal-title":"Cell Biol. Int."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00256","article-title":"Expression and contribution of NLRP3 inflammasome during the follicular development induced by PMSG.","volume":"7","author":"Zhang","year":"","journal-title":"Front. Cell Dev. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1111\/j.1740-0929.2010.00832.x","article-title":"Contribution of hypoxia-inducible factor-1\u03b1 to transcriptional regulation of vascular endothelial growth factor in bovine developing luteal cells.","volume":"82","author":"Zhang","year":"","journal-title":"Anim. Sci. J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.anireprosci.2011.03.002","article-title":"Activation of PI3K\/mTOR signaling pathway contributes to induction of vascular endothelial growth factor by hCG in bovine developing luteal cells.","volume":"125","author":"Zhang","year":"","journal-title":"Anim. Reprod. Sci."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.371","article-title":"Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1\u03b1 in mouse granulosa cells.","volume":"8","author":"Zhou","year":"2017","journal-title":"Cell Death Dis."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.631016\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T05:37:05Z","timestamp":1611293825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.631016\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,22]]},"references-count":33,"alternative-id":["10.3389\/fcell.2021.631016"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.631016","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,22]]},"article-number":"631016"}}