Mechanistic elucidation of angiogenesis mediated by Tspan18

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15625
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Keio University
• Principal Investigator: Tai Ikue 慶應義塾大学, 医学部(信濃町), 講師 (90749508)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: VEGF受容体 / angiogenesis / Tetraspanin18 / VEGFR2 / shedding / 血管新生

Outline of Final Research Achievements

Tspan18-dificient mice show abnormality in retinal vascular development. To understand how this phenotype is induced, binding of Tspan18 to VEGFRs was evaluated by co-immunoprecipitation assay. As a result, binding of Tspan18 to proteolytic fragments of VEGFR2, 130-kDa and 75-kDa fragments, was detected. Experiments using protease inhibitors showed that metalloprotease is necessary for the production of the 130-kDa fragment. Furthermore, it was shown that knockdown of Tspan18 in blood endothelial cells results in a shift in turnover of the fragments, including enhanced production of 130-kDa fragment and delayed production of 75-kDa fragment after VEGF treatment. Tumor blood vessels in Tspan18-deficient mice showed normalization of vascular structure, including absence of hemorrhage.

Free Research Field

血管生物学

Academic Significance and Societal Importance of the Research Achievements

血管形成において最も重要な受容体といえるVEGFR2はプロテアーゼにより断片へと切断されるが、この切断にどのような意味があるかはわかっていなかった。我々の研究により、Tspan18を欠損するマウスが血管形成に異常を示すことに加え、Tsapn18がVEGFR2の断片と結合することが明らかになり、VEGFR2の切断過程や断片の制御が正常な血管形成に重要であることが示唆された。