Basic study for preeclampsia therapeutics by phosphodiesterase-5 inhibitor

• Project/Area Number: 17K11233
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: Tomimatsu Takuji 大阪大学, 医学系研究科, 准教授 (30346209)
• Co-Investigator(Kenkyū-buntansha): 遠藤 誠之 大阪大学, 医学系研究科, 教授 (30644794) ; 味村 和哉 大阪大学, 医学系研究科, 助教 (50437422) ; 熊澤 惠一 東京大学, 医学部附属病院, 講師 (90444546)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 妊娠高血圧症候群 / 血管内皮障害 / 補体 / PDE5阻害薬 / PLGF / 血管新生因子 / PDE阻害薬 / 補体系 / PlGF / 血管内皮 / ｓFLT1 / sFlt1 / BeWo細胞 / 産科学

Outline of Final Research Achievements

Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunctionwith respect to the pathophysiology of preeclampsia. In addition, there has been compelling evidence that complement activation is implicated in the pathogenesis of preeclampsia.First, we showed that phosphodiesterase 5 (PDE5) inhibitor, vardenafil, stimulated the production of placental growth factor (PlGF) in Bewo cell line.Second, we evaluated a possible mechanism linking the complement system to angiogenic imbalance, in which PlGF stimulated the production of complement inhibitor CFH in endothelial cell line (HUVEC), and inhibiting CFH by SiRNA making these cells vulnerable to complement activation.
Noveltherapeutic strategies aimed at restoring angiogenic and complement system imbalance is expected to ameliorate complications and prolong gestation in women with preeclampsia.

Academic Significance and Societal Importance of the Research Achievements

妊娠高血圧症候群のメカニズムとしての抗血管新生状態に関する研究はすでに基礎・臨床ともに数多く存在しています。また近年、補体異常活性化の関与についての基礎的、臨床的検討の報告もなされ始めています。しかしながら、この両者、すなわち母体の抗血管新生状態と、補体の異常活性化の関連メカニズム（クロストーク）を検討した報告はほとんど見られません。一連の本研究の成果によって、両者の関連を示すメカニズムとその方法一端が明らかにすることで、抗血管新生状態と補体活性化を協調して制御することの重要性とその道筋を世界で初めて示すことになると期待しています。

Research Products

• [Journal Article] Efficacy of Prophylactic Antibiotics in Bakri Intrauterine Balloon Placement: A Single-Center Retrospective Analysis and Literature Review (2020)
  • Author(s): Nagase Y, Matsuzaki S, Kawanishi Y, Nakagawa S, Kakigano A, Takiuchi T, Mimura K, Tomimatsu T, Endo M, Kimura T.
  • Journal Title: American Journal of Perinatology Reports Volume: 10(1) Issue: 01 Pages: e106-e112
  • DOI: 10.1055/s-0040-1708487
  • Peer Reviewed / Open Access
• [Journal Article] Persistent funic presentation due to velamentous cord insertion adjacent to the internal os but not vasa previa (2020)
  • Author(s): Mimura Kazuya、Endo Masayuki、Matsuzaki Shinya、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: Taiwanese Journal of Obstetrics and Gynecology Volume: 59 Issue: 1 Pages: 167-168
  • DOI: 10.1016/j.tjog.2019.10.001
  • Peer Reviewed / Open Access
• [Journal Article] Successful management of fetal hemolytic disease due to strong anti-Rh17 with plasma exchange and intrauterine transfusion in a woman with the D--phenotype. (2020)
  • Author(s): Mimura K, Endo M, Takahashi A, Doi Y, Sakuragi M, Kiyokawa T, Taniguchi H, Kitabatake Y, Handa M, Tomimatsu T, Tomiyama Y, Isaka Y, Kimura T.
  • Journal Title: International Journal of Hematology Volume: 111 Issue: 1 Pages: 149-154
  • DOI: 10.1007/s12185-019-02735-6
  • Peer Reviewed / Open Access
• [Journal Article] Obstetric Outcomes of Pregnancy After Uterine Artery Embolization</p> (2020)
  • Author(s): Jitsumori Mariko、Matsuzaki Shinya、Endo Masayuki、Hara Takeya、Tomimatsu Takuji、Matsuzaki Satoko、Miyake Tatsuya、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Kobayashi Eiji、Ueda Yutaka、Kimura Tadashi
  • Journal Title: International Journal of Women's Health Volume: Volume 12 Pages: 151-158
  • DOI: 10.2147/ijwh.s236443
  • Peer Reviewed / Open Access
• [Journal Article] Systematic review on the needle and suture types for uterine compression sutures: a literature review (2019)
  • Author(s): Matsuzaki, S. Jitsumori, M. Hara, T. Matsuzaki ,S. Nakagawa, S. Miyake, T. Takiuchi, T. Kakigano, A. Kobayashi, E. Tomimatsu, T. Kimura, T.
  • Journal Title: BMC surgery. Volume: 19(1) Issue: 1 Pages: 196-196
  • DOI: 10.1186/s12893-019-0660-z
  • Peer Reviewed / Open Access
• [Journal Article] Horizontal Cervix as a Novel Sign for Predicting Adhesions on the Posterior Extrauterine Wall in Cases of Placenta Previa (2019)
  • Author(s): Matsuzaki Shinya、Okada Aiko、Endo Masayuki、Nagase Yoshikazu、Nakagawa Satoshi、Hiramatsu Kosuke、Kakigano Aiko、Mimura Kazuya、Takiuchi Tsuyoshi、Tomimatsu Takuji、Ueda Yutaka、Ogita Kazuhide、Kimura Tadashi
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 12 Pages: 2141-2141
  • DOI: 10.3390/jcm8122141
  • Peer Reviewed / Open Access
• [Journal Article] Endometrial carcinoma in a gravid uterus: a case report and literature review (2019)
  • Author(s): Shiomi Mayu、Matsuzaki Shinya、Kobayashi Eiji、Hara Takeya、Nakagawa Satoshi、Takiuchi Tsuyoshi、Mimura Kazuya、Ueda Yutaka、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: BMC Pregnancy and Childbirth Volume: 19 Issue: 1 Pages: 425-425
  • DOI: 10.1186/s12884-019-2489-y
  • Peer Reviewed / Open Access
• [Journal Article] Preeclampsia: Maternal Systemic Vascular Disorder Caused by Generalized Endothelial Dysfunction Due to Placental Antiangiogenic Factors (2019)
  • Author(s): Tomimatsu Takuji、Mimura Kazuya、Matsuzaki Shinya、Endo Masayuki、Kumasawa Keiichi、Kimura Tadashi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 17 Pages: 4246-4246
  • DOI: 10.3390/ijms20174246
  • Peer Reviewed / Open Access
• [Journal Article] Direct oral anticoagulants are effective and safe for the treatment of venous thromboembolism associated with gynecological cancers (2019)
  • Author(s): Shimizu Aasa、Sawada Kenjiro、Shiomi Mayu、Kawano Mahiru、Matsumoto Yuri、Takiuchi Tsuyoshi、Kodama Michiko、Kobayashi Eiji、Hashimoto Kae、Mabuchi Seiji、Ueda Yutaka、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: International Journal of Gynecology & Obstetrics Volume: 147 Issue: 2 Pages: 252-257
  • DOI: 10.1002/ijgo.12944
  • Peer Reviewed
• [Journal Article] Cervical cancer screening rate differs by HPV vaccination status: An interim analysis (2019)
  • Author(s): Taniguchi Mariko、Ueda Yutaka、Yagi Asami、Ikeda Sayaka、Endo Masayuki、Tomimatsu Takuji、Nakayama Tomio、Sekine Masayuki、Enomoto Takayuki、Kimura Tadashi
  • Journal Title: Vaccine Volume: 37 Issue: 32 Pages: 4424-4426
  • DOI: 10.1016/j.vaccine.2019.06.064
  • Peer Reviewed
• [Journal Article] Fetal Ultrasound Image in Persistent Fetal Vasculature (2019)
  • Author(s): Fukushima Yoko、Tomimatsu Takuji、Nishida Kohji
  • Journal Title: Ophthalmology Volume: 126 Issue: 7 Pages: 988-988
  • DOI: 10.1016/j.ophtha.2019.04.004
  • Peer Reviewed
• [Journal Article] Transcriptionally distinct mesenchymal stem/stromal cells circulate in fetus (2019)
  • Author(s): Shimbo, T., Endo, M., Iwai; S., Kitayama, T., Ouchi, Y., Yamamoto, R., Takaki, E., Yamazaki, S., Nishida, M., Wang, X., Kikuchi, Y., Tomimatsu, T., Kaneda, Y., Kimura, T. Tamai, K
  • Journal Title: Biochemical and Biophysical Research Communications Volume: pii: S0006-291X(19) Issue: 2 Pages: 30410-3
  • DOI: 10.1016/j.bbrc.2019.03.033
  • Peer Reviewed / Open Access
• [Journal Article] New dedicated blunt straight needles and sutures for uterine compression sutures: a retrospective study and literature review (2019)
  • Author(s): Matsuzaki Shinya、Endo Masayuki、Tomimatsu Takuji、Nakagawa Satoshi、Matsuzaki Satoko、Miyake Tatsuya、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Ueda Yutaka、Kimura Tadashi
  • Journal Title: BMC Surgery Volume: 19 Issue: 1 Pages: 33-33
  • DOI: 10.1186/s12893-019-0495-7
  • Peer Reviewed / Open Access
• [Journal Article] Radiotherapy for isolated recurrent epithelial ovarian cancer: A single institutional experience (2019)
  • Author(s): Komura Naoko、Mabuchi Seiji、Isohashi Fumiaki、Yokoi Eriko、Shimura Kotaro、Matsumoto Yuri、Kodama Michiko、Tomimatsu Takuji、Ogawa Kazuhiko、Kimura Tadashi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 6 Pages: 1173-1182
  • DOI: 10.1111/jog.13947
  • Peer Reviewed
• [Journal Article] Single versus multiple cervical dilation by osmotic dilator before induction of labor for second-trimester abortion (2019)
  • Author(s): Lee, M. Mimura, K. Endoh, M. Kawanishi, Y. Miyake, T. Kakigano, A. Takiuchi, T. Matsuzaki, S. Tomimatsu, T. Kimura, T.
  • Journal Title: J Obstet Gynaecol Res Volume: 45(5) Issue: 5 Pages: 961-966
  • DOI: 10.1111/jog.13930
  • Peer Reviewed / Open Access
• [Journal Article] A 3-year follow-up study of radiotherapy using computed tomography?based image-guided brachytherapy for cervical cancer (2019)
  • Author(s): Kawashima Atsushi、Isohashi Fumiaki、Mabuchi Seiji、Sawada Kenjiro、Ueda Yutaka、Kobayashi Eiji、Matsumoto Yuri、Otani Keisuke、Tamari Keisuke、Seo Yuji、Suzuki Osamu、Sumida Iori、Tomimatsu Takuji、Kimura Tadashi、Ogawa Kazuhiko
  • Journal Title: Journal of Radiation Research Volume: 60 Issue: 2 Pages: 264-269
  • DOI: 10.1093/jrr/rry104
  • Peer Reviewed / Open Access
• [Journal Article] Impact of maternal methylenetetrahydrofolate reductase C677T polymorphism on intervillous and decidual pathology with pregnancy loss. (2019)
  • Author(s): Mehandjiev TR, Tenno NM, Yanagihara I, et al.,
  • Journal Title: J Obstet Gynaecol Res Volume: 45 Issue: 1 Pages: 78-85
  • DOI: 10.1111/jog.13798
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Malignant transformation of uterine leiomyoma : suggested by clinical, imaging, histological, and genetic findings (2019)
  • Author(s): Tomimatsu T, Mabuchi S, Tsuboyama T, Hori Y, Sekine S, Kimura T.
  • Journal Title: European Journal of Gynaecological Oncology Volume: 40 Pages: 879-882
  • Peer Reviewed
• [Journal Article] Prenatal findings of serpentine-like syndrome with congenital intrathoracic stomach: differential diagnosis from congenital diaphragmatic hernia (2018)
  • Author(s): Mimura Kazuya、Endo Masayuki、Matsuoka Keiko、Tomimatsu Takuji、Tazuke Yuko、Okuyama Hiroomi、Takeuchi Makoto、Kimura Tadashi
  • Journal Title: Journal of Medical Ultrasonics Volume: 46 Issue: 2 Pages: 263-266
  • DOI: 10.1007/s10396-018-0896-8
  • Peer Reviewed / Open Access
• [Journal Article] A phase I/II study of GLIF combination chemotherapy for taxane/platinum-refractory/resistant endometrial cancer (GOGO-EM2) (2018)
  • Author(s): Tanaka Yusuke、Ueda Yutaka、Nakagawa Satoshi、Matsuzaki Shinya、Kobayashi Eiji、Shiki Yasuhiko、Nishio Yukihiro、Takemura Masahiko、Yamamoto Toshiya、Sawada Kenjiro、Tomimatsu Takuji、Yoshino Kiyoshi、Kimura Tadashi
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 82 Issue: 4 Pages: 585-592
  • DOI: 10.1007/s00280-018-3648-y
  • Peer Reviewed / Open Access
• [Journal Article] Obstetric outcomes and acceptance of alternative therapies to blood transfusion by Jehovah’s Witnesses in Japan: a single-center study (2018)
  • Author(s): Tanaka Mie、Matsuzaki Shinya、Endo Masayuki、Kakigano Aiko、Mimura Kazuya、Takiuchi Tsuyoshi、Miyake Tatsuya、Tomimatsu Takuji、Ueda Yutaka、Kimura Tadashi
  • Journal Title: International Journal of Hematology Volume: 108 Issue: 4 Pages: 432-437
  • DOI: 10.1007/s12185-018-2490-7
  • Peer Reviewed / Open Access
• [Journal Article] Arginase controls soluble vascular endothelial growth factor receptor 1 (sFlt1) to maintain pregnancy homeostasis (2018)
  • Author(s): Tanaka Hiroko、Kumasawa Keiichi、Kakigano Aiko、Mimura Kazuya、Endo Masayuki、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 499 Issue: 2 Pages: 150-155
  • DOI: 10.1016/j.bbrc.2018.03.086
  • Peer Reviewed / Open Access
• [Journal Article] Unresponsiveness to oxytocin due to an extremely thin uterine wall in a pregnant woman with systemic lupus erythematosus and Sj&ouml;gren's syndrome. (2018)
  • Author(s): Tomimatsu T, Hazama Y, Takeuchi M, Kimura T, Shimoya K.
  • Journal Title: J Obstet Gynaecol. Volume: 38 Issue: 2 Pages: 276-276
  • DOI: 10.1080/01443615.2017.1340439
  • Peer Reviewed
• [Journal Article] Successful anticoagulant therapy for disseminated intravascular coagulation during conservative management of placenta percreta: a case report and literature review (2017)
  • Author(s): Matsuzaki, S. Yoshino, K. Endo, M. Tomimatsu, T. Takiuchi, T. Mimura, K. Kumasawa, K. Ueda, Y. Kimura, T.
  • Journal Title: BMC Pregnancy Childbirth Volume: 17 Issue: 1 Pages: 443-443
  • DOI: 10.1186/s12884-017-1634-8
  • Peer Reviewed / Open Access
• [Journal Article] Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6) (2017)
  • Author(s): Yoshino K, Kamiura S, Yokoi T, Nakae R, Fujita M, Takemura M, Adachi K, Wakimoto A, Nishizaki T, Shiki Y, Tsutsui T, Kanda Y, Kobayashi E, Hashimoto K, Mabuchi S, Ueda Y, Sawada K, Tomimatsu T, Kimura T
  • Journal Title: Cancer Chemother Pharmacol Volume: 80 Issue: 6 Pages: 1239-47
  • DOI: 10.1007/s00280-017-3468-5
  • Peer Reviewed / Open Access
• [Journal Article] Investigation of perioperative complications associated with uterine compression sutures (2017)
  • Author(s): Suzuki, Y. Matsuzaki, S. Mimura, K. Kumasawa, K. Tomimatsu, T. Endo, M. Kimura, T.
  • Journal Title: Int J Gynaecol Obstet Volume: 139 Issue: 1 Pages: 28-33
  • DOI: 10.1002/ijgo.12249
  • Peer Reviewed
• [Journal Article] Predictors for recurrent/persistent high-grade intraepithelial lesions and cervical stenosis after therapeutic conization: a retrospective analysis of 522 cases. (2017)
  • Author(s): Tanaka Y, Ueda Y, Kakuda M, Kubota S, Matsuzaki S, Iwamiya T, Okazawa A, Matsuzaki S, Hashimoto K, Kobayashi E, Mabuchi S, Sawada K, Tomimatsu T, Yoshino K, Kimura T.
  • Journal Title: Int J Clin Oncol. Volume: 22 Issue: 5 Pages: 921-926
  • DOI: 10.1007/s10147-017-1124-z
  • Peer Reviewed
• [Journal Article] Pregnancy outcomes in women with different doses of corticosteroid supplementation during labor and delivery (2017)
  • Author(s): Owa, T. Mimura, K. Kakigano, A. Matsuzaki, S. Kumasawa, K. Endo, M. Tomimatsu, T. Kimura, T.
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Issue: 7 Pages: 1132-1138
  • DOI: 10.1111/jog.13336
  • Peer Reviewed / Open Access
• [Journal Article] Pure Primary Ovarian Squamous Cell Carcinoma Perforating the Rectum. (2017)
  • Author(s): Mimura K, Okada A, Haraguchi N, Sawada K, Tomimatsu T, Kimura T.
  • Journal Title: Case Rep Obstet Gynecol. Volume: 2017 Pages: 9793086-9793086
  • DOI: 10.1155/2017/9793086
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiology of preeclampsia: an angiogenic imbalance and long-lasting systemic vascular dysfunction. (2016)
  • Author(s): Tomimatsu T, Mimura K, Endo M, Kumasawa K, Kimura T.
  • Journal Title: Hypertens Res Volume: 40(4) Issue: 4 Pages: 305-310
  • DOI: 10.1038/hr.2016.152
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neglected shoulder presentation with foetal death managed by internal podalic version with nitroglycerine and sevoflurane. (2016)
  • Author(s): Sasano T, Tomimatsu T, Kanagawa T, Kimura T.
  • Journal Title: J Obstet Gynaecol. Volume: 6 Issue: 1 Pages: 1-2
  • DOI: 10.1080/01443615.2016.1239068
  • Peer Reviewed
• [Presentation] Fetal echocardiographic evaluation of dilated cardiomyopathy during mouse pregnancy (2018)
  • Author(s): Owa T, Miyoshi T, Kawanishi Y, Okada A, Kajimoto E, Tanaka H, Kakigano A, Mimura K, Endo M, Tomimatsu T, Kimura T.
  • Organizer: 第70回日本産科婦人科学会学術講演会
  • Int'l Joint Research