Summary of Research Project Results under JSPS FY2003
"Research for the Future Program"

1.Research Institution The University of Tokyo
2.Research Area Life Sciences
3.Research Field Angiogenesis and Vascular Development Control
4.Term of Project FY 2000 - FY 2003
5.Project Number 00L01305
6.Title of Project Studies on the Function of VEGF and Pathological Angiogenesis

7.Project Leader
Name Institution,Department Title of Position
Masabumi, Shibuya The University of Tokyo, The Institute of Medical Science Professor

8.Core Members

9.Summary of Research Results

1. Signal transduction from VEGF (vascular endothelial growth factor) receptors were examined in vitro and in vivo. We found that the VEGFR-2, a major signal transducer, utilizes PLCγ-PKC-MAP kinase pathway, but not (or only little) Ras pathway, for DNA synthesis. Furthermore, a single autophosphorylation site 1175-Tyr on VEGFR-2 is crucial for the activation of this signal pathway. A knock-in mouse which carries 1173 Tyr (corresponding to human 1175 Tyr) to Phe-mutation showed an embryonic lethality due to a severe vasculogenesis-defect.
2. A new member of VEGF family, VEGF-E which activates only VEGFR-2, was found to generate a 10-fold increased capillary networks in the subcutaneous tissues without severe side effects such as edema and hemorrhage, in K14-transgenic mouse system. In addition, domain analysis of VEGF-E with PlGF-chimeric constructs indicated that an interaction between loop-1 and loop-3 is essential, and about 50% of VEGF-E sequence can be replaced with human (PlGF) sequence. This information is important for application of VEGF-E as a treatment of ischemic diseases in the clinical field.
3. In a coculture system with HUVEC and normal human fibroblasts for tubular formation, we found that VEGF is essential for this formation, and non of the FGF, Ang1 or HGF alone could support this process.
4. We found that the physiological regression of blood vessels in rat pupillary membrane is induced by BMP4 secreted from lens as a paracrine manner, not by a reduction of VEGF levels.
5. VEGFR-1 gene in chicken was firstly isolated, thus the avian species conserve VEGFR-1, R-2 and R-3 system for angiogenesis. In addition, VEGFR-1 kinase was found to be involved in the progression of rheumatoid arthritis-like diseases in mice, suggesting VEGFR-1 as a new target for RA-treatment.

10.Key Words
(1)angiogenic factor  (2)VEGF  (3)VEGF-E 
(4)tyrosine kinase receptor  (5)Signal transduction  (6)vascular regression 
(7)BMP4  (8)rheumatoid arthritis  (9)VEGFR-1