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Mechanism of hypoxia-induced transformation in endothelial cells

Research Project

Project/Area Number 24590381
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionTottori University

Principal Investigator

TOMITA Shuhei  鳥取大学, 医学部, 教授 (00263898)

Co-Investigator(Kenkyū-buntansha) TAMAKI Toshiaki  徳島大学, 大学院ヘルスバイオサイエンス研究部, 教授 (80179879)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords血管内皮細胞 / 低酸素応答 / HIF / 肺高血圧症 / 転写因子 / 微小環境 / 酸化ストレス / 活性酸素 / 血管リモデリング
Outline of Final Research Achievements

Hypoxia-inducible factors (HIFs) in endothelial cells (ECs) help to maintain ECs and promote vascularization, and HIF-2α is abun- dantly expressed in ECs. However, the mechanisms of action of HIF-2α in ECs are not yet fully understood. The aim of this study was to evaluate the in vivo effects of overexpression of HIF-2α in ECs on skin flap survival. A random pattern skin flap was elevated on the dorsum of transgenic mice (Tg mice) with EC-specific HIF-2α conditional overexpression and wild-type littermate control mice. The HIF-2α mRNA and protein levels were significantly increased in the Tg mice when compared with control mice. Tg mice had significantly increased skin flap survival areas when compared with wild- type mice. Moreover, histological examination revealed an increase in the subcutaneous blood vessel counts in the Tg mice. Specific overexpression of HIF-2α in ECs promoted vascu- larization and enhanced skin flap survival in vivo in a mouse model.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (30 results)

All 2015 2014 2013 2012 Other

All Journal Article (17 results) (of which Peer Reviewed: 17 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results) Presentation (9 results) (of which Invited: 3 results) Book (3 results) Remarks (1 results)

  • [Journal Article] Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia.2015

    • Author(s)
      Miyamoto L, Yagi Y, Hatano A, Kawazoe K, Ishizawa K, Minakuchi K, Tomita S, Tsuchiya K.
    • Journal Title

      Biochim Biophys Acta

      Volume: 1850 Issue: 4 Pages: 640-646

    • DOI

      10.1016/j.bbagen.2014.12.006

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Overexpressed HIF-2α in Endothelial Cells Promotes Vascularization and Improves Random Pattern Skin Flap Survival.2014

    • Author(s)
      Morimoto A, Tomita S, Imanishi M, Shioi G, Kihira Y, Izawa-Ishizawa Y, Takaku M, Hashimoto I, Ikeda Y, Nakanishi H, Tamaki T.
    • Journal Title

      Plast Reconstr Surg Glob Open

      Volume: 7 Issue: 4 Pages: e132-e132

    • DOI

      10.1097/gox.0000000000000083

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Deletion of Hypoxia-Inducible Factor-1α in Adipocytes Enhances Glucagon-Like Peptide-1 Secretion and Reduces Adipose Tissue Inflammation2014

    • Author(s)
      Yoshitaka KIHIRA, Mariko MIYAKE, Manami HIRATA, Yoji HOSHINA, Kana KATO, Hitoshi SHIRAKAWA, Hiroshi SAKAUE, Noriko YAMANO, Yuki IZAWA-ISHIZAWA, Keisuke ISHIZAWA, Yasumasa IKEDA, Koichiro TSUCHIYA, Toshiaki TAMAKI, Shuhei TOMITA
    • Journal Title

      PLOS ONE

      Volume: 9 Issue: 4 Pages: e93856-e93856

    • DOI

      10.1371/journal.pone.0093856

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Smooth muscle cell-specific Hif-1α deficiency suppresses angiotensin II-induced vascular remodelling in mice.2014

    • Author(s)
      Imanishi M, Tomita S, Ishizawa K, Kihira Y, Ueno M, Izawa-Ishizawa Y, Ikeda Y, Yamano N, Tsuchiya K, Tamaki T.
    • Journal Title

      Cardiovasc Res

      Volume: in press Issue: 3 Pages: 460-468

    • DOI

      10.1093/cvr/cvu061

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] HIF-2α/ARNT complex regulates hair development via induction of p21Waf1/Cip1 and p27Kip1.2014

    • Author(s)
      Imamura Y, Tomita S, Imanishi M, Kihira Y, Ikeda Y, Ishizawa K, Tsuchiya K, Tamaki T.
    • Journal Title

      FASEB J

      Volume: in press Issue: 6 Pages: 2517-2524

    • DOI

      10.1096/fj.13-244079

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prostatic ischemia induces ventral prostatic hyperplasia in the SHR; possible mechanism of development of BPH.2014

    • Author(s)
      Saito M, Tsounapi P, Oikawa R, Shimizu S, Honda M, Sejima T, Kinoshita Y, Tomita S.
    • Journal Title

      Sci Rep

      Volume: 22 Issue: 1 Pages: 3822-3822

    • DOI

      10.1038/srep03822

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A.2014

    • Author(s)
      Sato S, Shirakawa H, Tomita S, Tohkin M, Gonzalez FJ, Komai M.
    • Journal Title

      Toxicol Appl Pharmacol

      Volume: 273(1) Issue: 1 Pages: 90-99

    • DOI

      10.1016/j.taap.2013.08.017

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Olmesartan ameliorates urinary dysfUnction in the spontaneously hypertensive rat via recovering bladder blood flow and decreasing oxidative stress2014

    • Author(s)
      Shimizu S, Saito M, Oiwa H, Ohmasa F, Tsounapi P, Oikawa R, Dimitriadis F, Martin TD, Satoh I, Kinoshita Y, Tomita S
    • Journal Title

      Neurourology and Urodynamics

      Volume: 33 Issue: 3 Pages: 350-7

    • DOI

      10.1002/nau.22405

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] The ARNT-STAT axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+cells.2013

    • Author(s)
      Nakajima K, Maekawa K, Kataoka K, Ishifune C, Nishida J, Arimochi H, Yoshimoto T, Tomita S, Nagahiro S, Yasutomo K.
    • Journal Title

      Nature Communications

      Volume: 4 Issue: 1 Pages: 1-11

    • DOI

      10.1038/ncomms3112

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Role of macrophage-derived hypoxia-inducible factor (HIF)-1α as a mediator of vascular remodelling2013

    • Author(s)
      Nakayama T, Kurobe H, Sugasawa N, Kinoshita H, Higashida M, Matsuoka Y, Yoshida Y, Hirata Y, Sakata M, Maxfield M, Shimabukuro M, Takahama Y, Sata M, Tamaki T, Kitagawa T, Tomita S.
    • Journal Title

      Cardiovasc Res

      Volume: 99 Issue: 4 Pages: 705-715

    • DOI

      10.1093/cvr/cvt146

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Dietary iron restriction inhibits progression of diabetic nephropathy in db/db mice.2013

    • Author(s)
      Ikeda Yasumasa, et al
    • Journal Title

      Am J Physiol Renal Physiol

      Volume: 304 Issue: 7 Pages: 1028-1036

    • DOI

      10.1152/ajprenal.00473.2012

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.2013

    • Author(s)
      Sakurada Takumi, et al
    • Journal Title

      Naunyn Schmiedebergs Arch Pharmacol

      Volume: 386 Issue: 1 Pages: 29-39

    • DOI

      10.1007/s00210-012-0810-7

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes.2012

    • Author(s)
      Ikeda Yasumasa, et al
    • Journal Title

      PLoS One

      Volume: 7 Issue: 7 Pages: e40465-e40465

    • DOI

      10.1371/journal.pone.0040465

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Systemic preconditioning by a prolyl hydroxylase inhibitor promotes prevention of skin flap necrosis via HIF-1-induced bone marrow-derived cells.2012

    • Author(s)
      Takaku Mitsuru, et al
    • Journal Title

      PLoS One

      Volume: 7 Issue: 8 Pages: e42964-e42964

    • DOI

      10.1371/journal.pone.0042964

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hypoxia inducible factor-1α is necessary for invasive phenotype in Vegf-deleted islet cell tumors.2012

    • Author(s)
      Takeda T
    • Journal Title

      Sci Rep

      Volume: 2 Issue: 1 Pages: 494-494

    • DOI

      10.1038/srep00494

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Heparin cofactor II, a serine protease inhibitor, promotes angiogenesis via activation of the AMPK-eNOS signaling pathway.2012

    • Author(s)
      Yasumasa Ikeda
    • Journal Title

      The Journal of Biological Chemistry

      Volume: 287 Issue: 41 Pages: 34256-34263

    • DOI

      10.1074/jbc.m112.353532

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Angiotensin II receptor blocker improves tumor necrosis factor-α-induced cytotoxicity via antioxidative effect in human glomerular endothelial cells.2012

    • Author(s)
      Izawa-Ishizawa Yuki, et al
    • Journal Title

      Pharmacology

      Volume: 90 Issue: 5-6 Pages: 324-331

    • DOI

      10.1159/000343244

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Pathophysiological responses to hypoxia in vascular remodeling by hypoxia-inducible factor-12015

    • Author(s)
      Shuhei Tomita
    • Organizer
      The 11th WORLD CONGRESS of the International Society fro ADAPTIVE MEDICINE
    • Place of Presentation
      Yonago, Japan
    • Year and Date
      2015-05-27 – 2015-05-30
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Iron restriction prevents progression of diabetic nephropathy.2012

    • Author(s)
      Ikeda Y
    • Organizer
      Keystone Symposia
    • Place of Presentation
      Beaver Run Resort, Co, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] HIF-1a is a determinant of insulin-dependent glucose uptake by skeletal muscle cells.2012

    • Author(s)
      Makino Y
    • Organizer
      Keystone Symposia
    • Place of Presentation
      Beaver Run Resort, Co, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] Hypoxia-inducible Factor-1α In Vascular Smooth Muscle Cells Regulates Angiotensin II-induced Vascular Remodeling And AT1 Receptor Expression In Mouse Aortic Media.2012

    • Author(s)
      Imanishi M
    • Organizer
      AHA scientific sessions 2012
    • Place of Presentation
      Convention center, California, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] Deficiency of Hypoxia Inducible Factor-1α in SM-22α-Expressing Bone Marrow-Derived Cells Alleviates Neointimal Formation Following Wire-induced Vascular Injury.2012

    • Author(s)
      Maeda Y
    • Organizer
      AHA scientific sessions 2012
    • Place of Presentation
      Convention center, California, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] Hypoxia-inducible factor-1α deficiency in smooth muscle cell attenuates angiotensin II-induced vascular remodeling in mice.2012

    • Author(s)
      Imanishi M
    • Organizer
      ISOTT 2012
    • Place of Presentation
      NOVOTEL Hotel, Bruges, Belgium
    • Related Report
      2012 Research-status Report
  • [Presentation] Role of Macrophagederived Hif-1α as a Mediator of Vascular Remodeling.2012

    • Author(s)
      Nakayama T
    • Organizer
      AHA scientific sessions 2012
    • Place of Presentation
      Convention center, California, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] Pathophysiological responses to hypoxia in vascular remodeling by hypoxia-inducible factors.2012

    • Author(s)
      Tomita S
    • Organizer
      ISOTT 2012
    • Place of Presentation
      NOVOTEL Hotel, Bruges, Belgium
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] 疾患に伴う血管リモデリング進展過程に置ける低酸素応答性転写因子HIFの役割2012

    • Author(s)
      冨田修平
    • Organizer
      第85回日本生化学会
    • Place of Presentation
      福岡国際会議場
    • Related Report
      2012 Research-status Report
    • Invited
  • [Book] 腎とフリーラジカル2012

    • Author(s)
      土屋浩一郎
    • Publisher
      東京医学社
    • Related Report
      2012 Research-status Report
  • [Book] 腎とフリーラジカル2012

    • Author(s)
      櫻田巧
    • Publisher
      東京医学社
    • Related Report
      2012 Research-status Report
  • [Book] 腎とフリーラジカル2012

    • Author(s)
      池田康将
    • Publisher
      東京医学社
    • Related Report
      2012 Research-status Report
  • [Remarks] 鳥取大学医学部分子薬理学分野HP

    • URL

      http://www.med.tottori-u.ac.jp/molpharm/6020.html

    • Related Report
      2014 Annual Research Report

URL: 

Published: 2013-05-31   Modified: 2019-07-29  

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