GPER mediates the IL6/JAK2/STAT3 pathway involved in VEGF expression in swine ovary GCs

in Journal of Molecular Endocrinology
View More View Less
  • 1 Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
  • | 2 Zhangjiagang Agriculture and Rural Affairs Bureau, Jiangsu, China
  • | 3 Department of Animal Husbandry and Veterinary, Beijing Vocational College of Agriculture, Beijing, China
  • | 4 National Grazing Headquarter, Beijing, China
  • | 5 Beijing Tianyuanaorui Bio-technology Limited, Beijing, China
  • | 6 Guangdong Polytechnic of Science and Trade, Guangdong, China

Correspondence should be addressed to X Wang or H Ni: xiangguo731@bua.edu.cn or nihemin@aliyun.com
Restricted access

Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis in ovaries, particularly during follicular development and ovulation. Interleukin-6 (IL-6) is one of the major pro-inflammatory factors that are involved in the angiogenesis process physiologically and pathologically. Previous studies have shown that 17β-estradiol (E2) stimulates VEGF expression by upregulating hypoxia-inducible factor 1α (HIF-1α) in many cell types, and the high level of E2 causes an inflammatory-like microenvironment before ovulation. However, whether IL-6 signaling is involved in E2-regulating VEGF expression in swine granulosa cells (GCs) is still unknown. In this study, we found the estrogen membrane receptor, G-protein-coupled estrogen receptor 1 (GPER), was expressed in swine GCs, and the expression level of GPER, HIF-1α, and VEGF increased with follicular development. In vitro study showed that E2, ICI182780, and GPER agonist (G1) promoted the expressions of HIF-1α and VEGF in swine GCs, while GPER antagonist (G15) inhibited the stimulating effect of E2 and G1. Meanwhile, G15 inhibited the stimulating effect of E2 and G1 on IL-6 mRNA expression and secretion. Furthermore, IL-6 antibody and AG490 (JAK2/STAT3 inhibitor) attenuated G1-induced HIF-1α and VEGF expression. In conclusion, this study revealed how estrogen-induced HIF-1α and VEGF expressions in swine GCs are mediated through GPER-derived IL-6 secretion leading to JAK2/STAT3 activation.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 794 794 794
Full Text Views 11 11 11
PDF Downloads 11 11 11
  • Abid H, Ryan ZC, Delmotte P, Sieck GC & Lanza IR 2020 Extramyocellular interleukin-6 influences skeletal muscle mitochondrial physiology through canonical JAK/STAT signaling pathways. FASEB Journal 34 1445814472. (https://doi.org/10.1096/fj.202000965RR)

    • Search Google Scholar
    • Export Citation
  • Araújo VR, Silva GM, Duarte AB, Magalhães DM, Almeida AP, Gonçalves RF, Bruno JB, Silva TF, Campello CC & Rodrigues AP et al.2011 Vascular endothelial growth factor-A(165) (VEGF-A(165)) stimulates the in vitro development and oocyte competence of goat preantral follicles. Cell and Tissue Research 346 273281. (https://doi.org/10.1007/s00441-011-1251-1)

    • Search Google Scholar
    • Export Citation
  • Babitha V, Panda RP, Yadav VP, Chouhan VS, Dangi SS, Khan FA, Singh G, Bag S, Taru Sharma G & Silvia WJ et al.2013 Amount of mRNA and localization of vascular endothelial growth factor and its receptors in the ovarian follicle during estrous cycle of water buffalo (Bubalus bubalis). Animal Reproduction Science 137 163176. (https://doi.org/10.1016/j.anireprosci.2013.01.004)

    • Search Google Scholar
    • Export Citation
  • Barboni B, Turriani M, Galeati G, Spinaci M, Bacci ML, Forni M & Mattioli M 2000 Vascular endothelial growth factor production in growing pig antral follicles. Biology of Reproduction 63 858864. (https://doi.org/10.1095/biolreprod63.3.858)

    • Search Google Scholar
    • Export Citation
  • Blasko E, Haskell CA, Leung S, Gualtieri G, Halks-Miller M, Mahmoudi M, Dennis MK, Prossnitz ER, Karpus WJ & Horuk R 2009 Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. Journal of Neuroimmunology 214 6777. (https://doi.org/10.1016/j.jneuroim.2009.06.023)

    • Search Google Scholar
    • Export Citation
  • Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K & Eberhardt C et al.1996 Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380 435439. (https://doi.org/10.1038/380435a0)

    • Search Google Scholar
    • Export Citation
  • Charnock-Jones DS, Clark DE, Licence D, Day K, Wooding FB & Smith SK 2001 Distribution of vascular endothelial growth factor (VEGF) and its binding sites at the maternal-fetal interface during gestation in pigs. Reproduction 122 753760. (https://doi.org/10.1530/rep.0.1220753)

    • Search Google Scholar
    • Export Citation
  • Che Q, Xiao X, Xu J, Liu M, Lu Y, Liu S & Dong X 2019 17β-Estradiol promotes endometrial cancer proliferation and invasion through IL-6 pathway. Endocrine Connections 8 961968. (https://doi.org/10.1530/EC-19-0258)

    • Search Google Scholar
    • Export Citation
  • De Francesco EM, Pellegrino M, Santolla MF, Lappano R, Ricchio E, Abonante S & Maggiolini M 2014 GPER mediates activation of HIF1α/VEGF signaling by estrogens. Cancer Research 74 40534064. (https://doi.org/10.1158/0008-5472.CAN-13-3590)

    • Search Google Scholar
    • Export Citation
  • Devesa J & Caicedo D 2019 The role of growth hormone on ovarian functioning and ovarian angiogenesis. Frontiers in Endocrinology 10 450. (https://doi.org/10.3389/fendo.2019.00450)

    • Search Google Scholar
    • Export Citation
  • Duffy DM, Ko C, Jo M, Brannstrom M & Curry TE 2019 Ovulation: parallels with inflammatory processes. Endocrine Reviews 40 369416. (https://doi.org/10.1210/er.2018-00075)

    • Search Google Scholar
    • Export Citation
  • Fortune JE, Rivera GM & Yang MY 2004 Follicular development: the role of the follicular microenvironment in selection of the dominant follicle. Animal Reproduction Science 82–83 109126. (https://doi.org/10.1016/j.anireprosci.2004.04.031)

    • Search Google Scholar
    • Export Citation
  • Gordon JD, Mesiano S, Zaloudek CJ & Jaffe RB 1996 Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation. Journal of Clinical Endocrinology and Metabolism 81 353359. (https://doi.org/10.1210/jcem.81.1.8550777)

    • Search Google Scholar
    • Export Citation
  • Grasselli F, Basini G, Bussolati S & Tamanini C 2002 Effects of VEGF and bFGF on proliferation and production of steroids and nitric oxide in porcine granulosa cells. Reproduction in Domestic Animals 37 362368. (https://doi.org/10.1046/j.1439-0531.2002.00386.x)

    • Search Google Scholar
    • Export Citation
  • Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS & Gallick GE 2005 HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24 31103120. (https://doi.org/10.1038/sj.onc.1208513)

    • Search Google Scholar
    • Export Citation
  • Greenaway J, Connor K, Pedersen HG, Coomber BL, LaMarre J & Petrik J 2004 Vascular endothelial growth factor and its receptor, Flk-1/KDR, are cytoprotective in the extravascular compartment of the ovarian follicle. Endocrinology 145 28962905. (https://doi.org/10.1210/en.2003-1620)

    • Search Google Scholar
    • Export Citation
  • Guimerà M, Morales-Ruiz M, Jiménez W & Balasch J 2009 LH/HCG stimulation of VEGF and adrenomedullin production by follicular fluid macrophages and luteinized granulosa cells. Reproductive Biomedicine Online 18 743749. (https://doi.org/10.1016/s1472-6483(1060021-1)

    • Search Google Scholar
    • Export Citation
  • Hamilton KJ, Hewitt SC, Arao Y & Korach KS 2017 Estrogen hormone biology. Current Topics in Developmental Biology 125 109146. (https://doi.org/10.1016/bs.ctdb.2016.12.005)

    • Search Google Scholar
    • Export Citation
  • He YY, Cai B, Yang YX, Liu XL & Wan XP 2009 Estrogenic G protein-coupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway. Cancer Science 100 10511061. (https://doi.org/10.1111/j.1349-7006.2009.01148.x)

    • Search Google Scholar
    • Export Citation
  • Heublein S, Lenhard M, Vrekoussis T, Schoepfer J, Kuhn C, Friese K, Makrigiannakis A, Mayr D & Jeschke U 2012 The G-protein-coupled estrogen receptor (GPER) is expressed in normal human ovaries and is upregulated in ovarian endometriosis and pelvic inflammatory disease involving the ovary. Reproductive Sciences 19 11971204. (https://doi.org/10.1177/1933719112446085)

    • Search Google Scholar
    • Export Citation
  • Hunter CA & Jones SA 2015 IL-6 as a keystone cytokine in health and disease. Nature Immunology 16 448457. (https://doi.org/10.1038/ni.3153)

  • Irusta G, Abramovich D, Parborell F & Tesone M 2010 Direct survival role of vascular endothelial growth factor (VEGF) on rat ovarian follicular cells. Molecular and Cellular Endocrinology 325 93100. (https://doi.org/10.1016/j.mce.2010.04.018)

    • Search Google Scholar
    • Export Citation
  • Jolly PD, Smith PR, Heath DA, Hudson NL, Lun S, Still LA, Watts CH & McNatty KP 1997 Morphological evidence of apoptosis and the prevalence of apoptotic versus mitotic cells in the membrana granulosa of ovarian follicles during spontaneous and induced atresia in ewes. Biology of Reproduction 56 837846. (https://doi.org/10.1095/biolreprod56.4.837)

    • Search Google Scholar
    • Export Citation
  • Jung JE, Lee HG, Cho IH, Chung DH, Yoon SH, Yang YM, Lee JW, Choi S, Park JW & Ye SK et al.2005 STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB Journal 19 12961298. (https://doi.org/10.1096/fj.04-3099fje)

    • Search Google Scholar
    • Export Citation
  • Keck C, Rajabi Z, Pfeifer K, Bettendorf H, Brandstetter T & Breckwoldt M 1998 Expression of interleukin-6 and interleukin-6 receptors in human granulosa lutein cells. Molecular Human Reproduction 4 10711076. (https://doi.org/10.1093/molehr/4.11.1071)

    • Search Google Scholar
    • Export Citation
  • Kumari N, Dwarakanath BS, Das A & Bhatt AN 2016 Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biology 37 1155311572. (https://doi.org/10.1007/s13277-016-5098-7)

    • Search Google Scholar
    • Export Citation
  • Lin P & Rui R 2010 Effects of follicular size and FSH on granulosa cell apoptosis and atresia in porcine antral follicles. Molecular Reproduction and Development 77 670678. (https://doi.org/10.1002/mrd.21202)

    • Search Google Scholar
    • Export Citation
  • Machelon V, Emilie D, Lefevre A, Nome F, Durand-Gasselin I & Testart J 1994 Interleukin-6 biosynthesis in human preovulatory follicles: some of its potential roles at ovulation. Journal of Clinical Endocrinology and Metabolism 79 633642. (https://doi.org/10.1210/jcem.79.2.7519193)

    • Search Google Scholar
    • Export Citation
  • Neulen J, Raczek S, Pogorzelski M, Grunwald K, Yeo TK, Dvorak HF, Weich HA & Breckwoldt M 1998 Secretion of vascular endothelial growth factor/vascular permeability factor from human luteinized granulosa cells is human chorionic gonadotrophin dependent. Molecular Human Reproduction 4 203206. (https://doi.org/10.1093/molehr/4.3.203)

    • Search Google Scholar
    • Export Citation
  • Nichols JA, Perego MC, Schütz LF, Hemple AM & Spicer LJ 2019 Hormonal regulation of vascular endothelial growth factor A (VEGFA) gene expression in granulosa and theca cells of cattle1. Journal of Animal Science 97 30343045. (https://doi.org/10.1093/jas/skz164)

    • Search Google Scholar
    • Export Citation
  • Nishigaki A, Okada H, Okamoto R, Sugiyama S, Miyazaki K, Yasuda K & Kanzaki H 2011 Concentrations of stromal cell-derived factor-1 and vascular endothelial growth factor in relation to the diameter of human follicles. Fertility and Sterility 95 742746. (https://doi.org/10.1016/j.fertnstert.2010.10.028)

    • Search Google Scholar
    • Export Citation
  • Ortega HH, Salvetti NR, Amable P, Dallard BE, Baravalle C, Barbeito CG & Gimeno EJ 2007 Intraovarian localization of growth factors in induced cystic ovaries in rats. Anatomia, Histologia, Embryologia 36 94102. (https://doi.org/10.1111/j.1439-0264.2006.00726.x)

    • Search Google Scholar
    • Export Citation
  • Palma-Vera SE, Schoen J & Chen S 2017 Periovulatory follicular fluid levels of estradiol trigger inflammatory and DNA damage responses in oviduct epithelial cells. PLoS ONE 12 e0172192. (https://doi.org/10.1371/journal.pone.0172192)

    • Search Google Scholar
    • Export Citation
  • Sant’Ana F, Reis Junior JL, Blume GR, Gimeno EJ, Rey F & Ortega HH 2015 Immunohistochemical expression of growth factors in the follicular wall of normal and cystic ovaries of sows. Reproduction in Domestic Animals 50 327332. (https://doi.org/10.1111/rda.12495)

    • Search Google Scholar
    • Export Citation
  • Shao R, Nutu M, Karlsson-Lindahl L, Benrick A, Weijdegård B, Lager S, Egecioglu E, Fernandez-Rodriguez J, Gemzell-Danielsson K & Ohlsson C et al.2009 Downregulation of cilia-localized IL-6R alpha by 17beta-estradiol in mouse and human fallopian tubes. American Journal of Physiology: Cell Physiology 297 C140C151. (https://doi.org/10.1152/ajpcell.00047.2009)

    • Search Google Scholar
    • Export Citation
  • Shimizu T & Miyamoto A 2007 Progesterone induces the expression of vascular endothelial growth factor (VEGF) 120 and Flk-1, its receptor, in bovine granulosa cells. Animal Reproduction Science 102 228237. (https://doi.org/10.1016/j.anireprosci.2006.11.012)

    • Search Google Scholar
    • Export Citation
  • Shimizu T, Jiang JY, Sasada H & Sato E 2002 Changes of messenger RNA expression of angiogenic factors and related receptors during follicular development in gilts. Biology of Reproduction 67 18461852. (https://doi.org/10.1095/biolreprod.102.006734)

    • Search Google Scholar
    • Export Citation
  • Shimizu T, Jayawardana BC, Tetsuka M & Miyamoto A 2007 Differential effect of follicle-stimulating hormone and estradiol on expressions of vascular endothelial growth factor (VEGF) 120, VEGF164 and their receptors in bovine granulosa cells. Journal of Reproduction and Development 53 105112. (https://doi.org/10.1262/jrd.18088)

    • Search Google Scholar
    • Export Citation
  • Słomczyńska M & Woźniak J 2001 Differential distribution of estrogen receptor-beta and estrogen receptor-alpha in the porcine ovary. Experimental and Clinical Endocrinology and Diabetes 109 238244. (https://doi.org/10.1055/s-2001-15112)

    • Search Google Scholar
    • Export Citation
  • Smith HO, Stephens ND, Qualls CR, Fligelman T, Wang T, Lin CY, Burton E, Griffith JK & Pollard JW 2013 The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma. Molecular Oncology 7 4154. (https://doi.org/10.1016/j.molonc.2012.07.002)

    • Search Google Scholar
    • Export Citation
  • Straub RH 2007 The complex role of estrogens in inflammation. Endocrine Reviews 28 521574. (https://doi.org/10.1210/er.2007-0001)

  • Tang ZR, Zhang R, Lian ZX, Deng SL & Yu K 2019 Estrogen-receptor expression and function in female reproductive disease. Cells 8 1123. (https://doi.org/10.3390/cells8101123)

    • Search Google Scholar
    • Export Citation
  • Tirpe AA, Gulei D, Ciortea SM, Crivii C & Berindan-Neagoe I 2019 Hypoxia: overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes. International Journal of Molecular Sciences 20 6140. (https://doi.org/10.3390/ijms20246140)

    • Search Google Scholar
    • Export Citation
  • Trau HA, Brännström M, Curry TE & Duffy DM 2016 Prostaglandin E2 and vascular endothelial growth factor A mediate angiogenesis of human ovarian follicular endothelial cells. Human Reproduction 31 436444. (https://doi.org/10.1093/humrep/dev320)

    • Search Google Scholar
    • Export Citation
  • Wu J, Richer J, Horwitz KB & Hyder SM 2004 Progestin-dependent induction of vascular endothelial growth factor in human breast cancer cells: preferential regulation by progesterone receptor B. Cancer Research 64 22382244. (https://doi.org/10.1158/0008-5472.can-03-3044)

    • Search Google Scholar
    • Export Citation
  • Xiao L, Hu J, Song L, Zhang Y, Dong W, Jiang Y, Zhang Q, Yuan L & Zhao X 2019 Profile of melatonin and its receptors and synthesizing enzymes in cumulus-oocyte complexes of the developing sheep antral follicle-a potential estradiol-mediated mechanism. Reproductive Biology and Endocrinology 17 1. (https://doi.org/10.1186/s12958-018-0446-7)

    • Search Google Scholar
    • Export Citation
  • Yan Z, Weich HA, Bernart W, Breckwoldt M & Neulen J 1993 Vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) expression in luteinized human granulosa cells in vitro. Journal of Clinical Endocrinology and Metabolism 77 17231725. (https://doi.org/10.1210/jcem.77.6.8263163)

    • Search Google Scholar
    • Export Citation
  • Yang M, Wang L, Wang X, Wang X, Yang Z & Li J 2017 IL-6 promotes FSH-induced VEGF expression Through JAK/STAT3 signaling pathway in bovine granulosa cells. Cellular Physiology and Biochemistry 44 293302. (https://doi.org/10.1159/000484885)

    • Search Google Scholar
    • Export Citation
  • Zhang L, Xiong W, Li N, Liu H, He H, Du Y, Zhang Z & Liu Y 2017 Estrogen stabilizes hypoxia-inducible factor 1α through G protein-coupled estrogen receptor 1 in eutopic endometrium of endometriosis. Fertility and Sterility 107 439447. (https://doi.org/10.1016/j.fertnstert.2016.11.008)

    • Search Google Scholar
    • Export Citation
  • Zhang Z, Qin P, Deng Y, Ma Z, Guo H, Guo H, Hou Y, Wang S, Zou W & Sun Y et al.2018 The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation. Journal of Neuroinflammation 15 206. (https://doi.org/10.1186/s12974-018-1246-x)

    • Search Google Scholar
    • Export Citation
  • Zhang H, Wei Q, Gao Z, Ma C, Yang Z, Zhao H, Liu C, Liu J, Zhao X & Ma B 2019 G protein-coupled receptor 30 mediates meiosis resumption and gap junction communications downregulation in goat cumulus-oocyte complexes by 17β-estradiol. Journal of Steroid Biochemistry and Molecular Biology 187 5867. (https://doi.org/10.1016/j.jsbmb.2018.11.001)

    • Search Google Scholar
    • Export Citation