Structure and function of VEGF receptors related to preeclampsia.

• Project/Area Number: 17390110
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: SHIBUYA Masabumi The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (10107427)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥13,100,000 (Direct Cost: ¥13,100,000); Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000); Fiscal Year 2005: ¥6,800,000 (Direct Cost: ¥6,800,000)
• Keywords: angiogenesis / VEGF / VEGF receptor / renal dysfunction / VEGF受容体-1 / 妊娠 / 胎盤 / trophoblast stem cells / RNAi

Research Abstract

Preeclampsia is a major disease in gynecological field. Recent studies strongly suggest that soluble form of Flt-1 (sFlt-1/sVEGFR1) is deeply involved in this disease. We attempted to understand the whole functions of Flt-1 protein including sFlt-1.
1, We found that trophoblast stem cell (TS cell) system could be a good model for flt-1 gene expression, since in placenta, trophoblast cells are the major producer for sFlt-1. During the differentiation, flt-1 mRNA was 5-fold elevated, suggesting a physiological gene expression. However, we could not find a stress which abnormally upregulate the expression of sflt-l. Such a stress could be a candidate for inducer of preeclampsia.
2, We examined the effect of exogenous VEGF-A and sFlt-1 on pregnant mice. We found that exogenous VEGF-A induces pathological change at placenta such as fibrin deposition, and exogenous sFlt-1 transiently induces hypertension and proteinurea. However, to maintain these phenotypes, a large amount of sFlt-1 appears to be required.
3, sFlt-1 protein efficiently blocked abnormally secreted VEGF-A from ascites tumors, resulting in suppression of ascites volume and tumor growth in ascites. Thus, sFlt-1 protein is a good candidate for an inhibitor of pathological VEGF-A and ascites tumor.
4, Flt-1 signaling-deficient mice (Flt-1 TK-/- mice) showed a milder phenotype in arthritis-model, indicating that tyrosine kinase of Flt-1 is a new target for the treatment of rheumatoid arthritis.
Dr.Ambati' s group collaborating with us found that sFlt-1 is an important natural molecule for maintaining avascularity in cornea.

Research Products

• [Journal Article] Vascular Endothelial Growth Factor (VEGF)-Receptor2 : Its Biological Functions, Major Signaling Pathway, and Specific Ligand VEGF-E. Endothelium (2006)
  • Author(s): Shibuya M.
  • Journal Title: Endothelium 13 Pages: 63-69
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vascular endothelial growth factor receptor-1 (VEGFRl/Flt-1) : a dual regulator for angiogenesis (2006)
  • Author(s): Shibuya M.
  • Journal Title: Angiogenesis (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Corneal avascularity is due to soluble VEGF receptor-1 (2006)
  • Author(s): Ambati BK. et al.
  • Journal Title: Nature 443 Pages: 993-997
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages (2006)
  • Author(s): Murakami M. et al.
  • Journal Title: Blood 108 Pages: 1849-1856
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vascular Endothelial Growth Factor (VEGF)-Receptor2 : Its Biological Functions, Major Signaling Pathway, and Specific Ligand VEGF-E. (2006)
  • Author(s): Shibuya M.
  • Journal Title: Endothelium. 13 Pages: 63-69
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vascular endothelial growth factor receptor-1 (VEGFR1/Flt-1) : a dual regulator for angiogenesis. (2006)
  • Author(s): Shibuya, M.
  • Journal Title: Angiogenesis 9 Pages: 225-230
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages (2006)
  • Author(s): Murakami, M., Iwai, S., Hiratsuka, S., Yamauchi, M., Nakamura, K., Iwakura, Y., Shibuya, M.
  • Journal Title: Blood 108 Pages: 1849-1856
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Corneal avascularity is due to soluble VEGF receptor-1. (2006)
  • Author(s): Ambati BK, Nozaki M, Singh N, et al., Khurana TS, Shibuya M, Baldwin ME, Ferrara N, Gerber HP, De Falco S, Witta J, Baffi JZ, Raisler BJ, Ambati J.
  • Journal Title: Nature 443 Pages: 993-997
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vascular Endothelial Growth Factor (VEGF)-Receptor2 : Irs Biological Functions, Major Signaling Pathway, and Specific Ligand VEGF-E. Endothelium (2006)
  • Author(s): Shibuya M.
  • Journal Title: Endothelium 13 Pages: 63-69
• [Journal Article] Vascular endothelial growth factor receptor-1 (VEGFR1/Flt-1) : a dual regulator for angiogenesis (2006)
  • Author(s): Shibuya M.
  • Journal Title: Angiogenesis (in press)
• [Journal Article] Corneal avascularity is due to soluble VEGF receptor-1 (2006)
  • Author(s): Ambati BK., et al.
  • Journal Title: Nature 443 Pages: 993-997
• [Journal Article] VEGF-A is involved in guidance of VEGF-receptor-positive cells to the anterior portion of early embryos. (2005)
  • Author(s): Hiratsuka, S., Kataoka, Y., Nakao, K., Nakamura, K., Morikawa, S., Tanaka, S., Katsuki, M., Maru, Y., Shibuya, M.
  • Journal Title: Mol.Cell.Biol. 25 Pages: 335-363
• [Journal Article] Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. (2005)
  • Author(s): Wada, S., Tsunoda, T., Baba, T., Primus, J., Kuwano, H., Shibuya, M., Tahara, H.
  • Journal Title: Cancer Res. 65 Pages: 4939-4946
• [Journal Article] Vascular endothelial growth factor receptor-1 signaling is essential for osteoclast development and bone-marrow formation in CSF-1-deficient mice. (2005)
  • Author(s): Niida, S., Kondo, T., Hiratsuka, S., Hayashi, S.-I., Amizuka, N., Noda, T., Ikeda, K., Shibuya, M.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 102 Pages: 14016-14021
• [Journal Article] Locating inositol 1,4,5-trisphosphate in the nucleus and neuronal dendrites with genetically encoded fluorescent indicators. (2005)
  • Author(s): Sato, M., Ueda, Y., Shibuya, M., Umezawa, Y.
  • Journal Title: Anal Chem. 77 Pages: 4751-4758
• [Journal Article] The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. (2005)
  • Author(s): Takahashi H, Shibuya M.
  • Journal Title: Clin Sci(Lond). 109 Pages: 227-241