A role of endoplasmic reticulum stress in ovarian angiogenesis

• Project/Area Number: 26462476
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: Harada Miyuki 東京大学, 医学部附属病院, 講師 (70451812)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 卵巣 / 血管新生 / 小胞体ストレス応答 / 血管内皮増殖因子 / 卵巣過剰刺激症候群

Outline of Final Research Achievements

Vascular endothelial growth factor A (VEGFA) is crucial for ovarian angiogenesis, but its excess production induces ovarian hyperstimulation syndrome (OHSS). The aim of this study was to determine whether endoplasmic reticulum (ER) stress regulates VEGFA expression in granulosa cells, and whether its activation is involved in OHSS development. The expression of the spliced form of X-box-binding protein 1 [XBP1(S)], induced by ER stress, in cumulus cells from OHSS patients was higher than non-OHSS patients. The ER stress inducer tunicamycin increased hCG-induced VEGFA production in human granulosa cells through the induction of XBP1(S), and pretreatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) abrogated the effect of tunicamycin. In OHSS model rats, TUDCA administration prevented the OHSS development. Our findings suggest ER stress upregulates hCG-induced VEGFA production in granulosa cells, indicating that ER stress might be involved in OHSS development.

Research Products

• [Int'l Joint Research] 大連医科大学附属第二病院(中国)
• [Journal Article] A Potential Role for Endoplasmic Reticulum Stress in Progesterone Deficiency in Obese Women. (2017)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Azhary JM, Yoshino O, Izumi G, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Endocrinology Volume: 158 Pages: 84-97
  • DOI: 10.1210/en.2016-1511
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Emerging Role of FOXL2 in Regulating the Transcriptional Activation Function of Estrogen Receptor β: An Insight Into Ovarian Folliculogenesis. (2017)
  • Author(s): Hirano M, Wada-Hiraike O, Fu H, Akino N, Isono W, Sakurabashi A, Fukuda T, Morita Y, Tanikawa M, Miyamoto Y, Nishi Y, Yanase T, Harada M, Oishi H, Yano T, Koga K, Oda K, Kawana K, Fujii T, Osuga Y.
  • Journal Title: Reprod Sci Volume: 24 Issue: 1 Pages: 133-141
  • DOI: 10.1177/1933719116651150
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Usefulness of T2 star-weighted imaging in ovarian cysts and tumors. (2016)
  • Author(s): Takahashi N, Yoshino O, Maeda E, Naganawa S, Harada M, Koga K, Hiraike O, Nakamura M, Tabuchi T, Hori M, Saito S, Fujii T, Osuga Y.
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Issue: 10 Pages: 1336-1342
  • DOI: 10.1111/jog.13056
  • Peer Reviewed
• [Journal Article] Where are oncofertility and fertility preservation treatments heading in 2016? (2016)
  • Author(s): Harada M, Osuga Y.
  • Journal Title: Future Oncol Volume: 12 Issue: 20 Pages: 2313-2321
  • DOI: 10.2217/fon-2016-0161
  • Peer Reviewed
• [Journal Article] A potential role of endoplasmic reticulum stress in development of ovarian hyperstimulation syndrome. (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Yoshino O, Urata Y, Izumi G, Takamura M, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Mol Cell Endocrinol Volume: 428 Pages: 161-169
  • DOI: 10.1016/j.mce.2016.03.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cyclic Stretch Augments Production of Neutrophil Chemokines, Matrix Metalloproteinases, and Activin A in Human Endometrial Stromal Cells. (2015)
  • Author(s): Izumi G, Koga K, Takamura M, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: epub Issue: 6 Pages: 501-506
  • DOI: 10.1111/aji.12359
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Laparoscopic excision of ovarian endometrioma does not exert a qualitative effect on ovarian function: insights from in vitro fertilization and single embryo transfer cycles. (2015)
  • Author(s): Harada M, Takahashi N, Hirata T, Koga K, Fujii T, Osuga Y
  • Journal Title: J Assist Reprod Genet Volume: 32(5) Issue: 5 Pages: 685-9
  • DOI: 10.1007/s10815-015-0457-7
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells. (2015)
  • Author(s): Miyashita, M., Koga, K., Izumi, G., Makabe, T., Hasegawa, A., Hirota, Y., Hirata, T., Harada, M., Fujii, T., Osuga, Y
  • Journal Title: Fertility and Sterility Volume: 104 Issue: 1 Pages: 217-24
  • DOI: 10.1016/j.fertnstert.2015.03.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Four Cases of Postoperative Pneumothorax Among 2814 Consecutive Laparoscopic Gynecologic Surgeries: A Possible Correlation Between Postoperative Pneumothorax and Endometriosis. (2015)
  • Author(s): Hirata T, Nakazawa A, Fukuda S, Hirota Y, Izumi G, Takamura M, Harada M, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Minim Invasive Gynecol Volume: 22 Issue: 6 Pages: 980-984
  • DOI: 10.1016/j.jmig.2015.04.023
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Evidence of the activation of unfolded protein response in granulosa and cumulus cells during follicular growth and maturation. (2015)
  • Author(s): Harada, M., Nose, E., Takahashi, N., Hirota, Y., Hirata, T., Yoshino, O., Koga, K., Fujii, T., Osuga, Y
  • Journal Title: Gynecological Endocrinology Volume: 31 Issue: 10 Pages: 783-787
  • DOI: 10.3109/09513590.2015.1062862
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simultaneous Detection and Evaluation of Four Subsets of CD4+ T Lymphocyte in Lesions and Peripheral Blood in Endometriosis. (2015)
  • Author(s): Takamura, M., Koga, K., Izumi, G., Hirata, T., Harada, M., Hirota, Y., Hiraike, O., Fujii, T., Osuga, Y
  • Journal Title: American Journal of Reproductive Immunology Volume: 74 Issue: 6 Pages: 480-486
  • DOI: 10.1111/aji.12426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The outcome of infertility treatment in patients undergoing assisted reproductive technology after conservative therapy for endometrial cancer. (2014)
  • Author(s): Fujimoto A, Ichinose M, Harada M, Hirata T, Osuga Y, Fujii T.
  • Journal Title: J Assist Reprod Genet Volume: 31 Issue: 9 Pages: 1189-94
  • DOI: 10.1007/s10815-014-0297-x
  • Peer Reviewed
• [Journal Article] IL-1β increases expression of tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells. (2014)
  • Author(s): Urata Y, Koga K, Hirota Y, Akiyama I, Izumi G, Takamura M, Nagai M, Harada M, Hirata T, Yoshino O, Kawana K, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol. Volume: 72 Issue: 5 Pages: 496-503
  • DOI: 10.1111/aji.12282
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of dienogest in the treatment of symptomatic adenomyosis: a pilot study. (2014)
  • Author(s): Hirata T, Izumi G, Takamura M, Fujii T, Osuga Y.
  • Journal Title: Gynecol Endocrinol Volume: 30 Issue: 10 Pages: 726729-726729
  • DOI: 10.3109/09513590.2014.926882
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis. (2014)
  • Author(s): Miyashita M, Koga K, Takamura M, Izumi G, Nagai M, Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y.
  • Journal Title: Gynecol Endocrinol. Volume: 30 Issue: 9 Pages: 644-648
  • DOI: 10.3109/09513590.2014.911279
  • Peer Reviewed / Open Access
• [Journal Article] Bone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cells. (2014)
  • Author(s): Akiyama I, Yoshino O et al.
  • Journal Title: Reprod Sci. Volume: 21(4) Issue: 4 Pages: 477-82
  • DOI: 10.1177/1933719113503411
  • Peer Reviewed
• [Presentation] 卵巣過剰刺激症候群における小胞体ストレス応答の役割と小胞体ストレス抑制剤の予防的効果 (2016)
  • Author(s): 高橋 望、原田 美由紀、廣田 泰、平池 修、泉 玄太郎、高村 将司、平田 哲也、甲賀 かをり、大須賀 穣、藤井 知行
  • Organizer: 第61回日本生殖医学学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-03
• [Presentation] 私はこうする：ART診療実践講座7 当科におけるラボ管理とリスク対策ーよりよい妊娠率と合併症の減少を目指してー (2016)
  • Author(s): 大井なぎさ 原田美由紀 平田哲也 中澤明里 平野茉来 秋山育美 金谷真由子 山本直子 泉玄太郎 堤亮 大須賀穣 藤井知行
  • Organizer: 第61回日本生殖医学学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-03
• [Presentation] 高齢不妊症患者に対する治療戦略としてのARTと子宮筋腫核出術とのコンビネーション療法：卵巣加齢の影響を最小限にするための戦略 (2016)
  • Author(s): 田邉良介、原田美由紀、大井なぎさ、平田哲也、泉玄太郎、高橋望、金谷真由子、山本直子、堤亮、廣田泰、甲賀かをり、平池修、大須賀穣、藤井知行
  • Organizer: 第61回日本生殖医学学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-03
• [Presentation] Endoplasmic reticulum (ER) stress induces vascular endothelial growth factor (VEGF) production in granulosa cells: implications for a novel therapeutic approach for OHSS (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Yoshino O, Urata Y, Izumi G, Takamura M, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y
  • Organizer: 68th Annual Congress of the Japan Society of Obstetrics and Gynwcology
  • Place of Presentation: 東京
  • Year and Date: 2016-04-21
  • Int'l Joint Research
• [Presentation] Endoplasmic reticulum stress induces vascular endothelial growth factor production in granulosa cells: implications for a novel therapeutic approach for ovarian hyperstimulation syndrome (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Yoshino O, Hiraike O, Fujii T, Osuga Y
  • Organizer: 98th The Endocrine Society's Annual Meeting
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Presentation] Endoplasmic reticulum stress induces VEGF production in granulosa cells: implications for a novel therapeutic approach for OHSS (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Yoshino O, Hiraike O, Fujii T, Osuga Y
  • Organizer: 98thENDO
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Presentation] Laparoscopic excision of ovarian endometrioma may exert quantitative but not qualitative effects on affected ovaries in IVF settings (2014)
  • Author(s): Harada M, Oi N, Hirata T, Koga K, Fujii T, Osuga Y
  • Organizer: 96th The Endocrine Society's Annual Meeting
  • Place of Presentation: シカゴ（米国）
  • Year and Date: 2014-06-21 – 2014-06-24