Kubota, Yoshiaki

写真a

Affiliation

School of Medicine, Department of Anatomy (Shinanomachi)

Position

Professor

Related Websites

External Links

Career 【 Display / hide

  • 2000.04
    -
    2002.03

    School of Medicine, Keio University, Dept of Plastic Surgery, resident

  • 2006.04
    -
    2008.10

    School of Medicine, Keio University, Dept of Cell Differentiation, Non-tenured instructor

  • 2008.11
    -
    2013.03

    School of Medicine, Keio University, Center for Integrated Medical Research (Keio Kanrinmaru Project), Tenure track assistant professor

  • 2011.12
    -
    2012.07

    National Institutes of Health, Laboratory of Stem Cell and Neurovascular Development and Patterning, Visiting Researcher

  • 2013.04
    -
    2015.04

    School of Medicine, Keio University, The Laboratory of Vascular Biology, Principal Investigator (Associate professor)

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Academic Background 【 Display / hide

  • 1994.04
    -
    2000.03

    Keio University, School of Medicine

    JAPAN, University, Graduated, Other

  • 2003.04
    -
    2006.03

    Keio University, School of Medicine

    JAPAN, Graduate School, Skipped grade(s), Doctoral course

Academic Degrees 【 Display / hide

  • 医学博士, Keio University, Coursework, 2006.03

Licenses and Qualifications 【 Display / hide

  • MD, 2000.05

 

Research Areas 【 Display / hide

  • Developmental biology

  • Morphology/Structure (Vascular biology)

  • General anatomy (including histology/embryology)

Research Keywords 【 Display / hide

  • angiogenesis

  • VEGF

  • retina

  • Plastic surgery

Research Themes 【 Display / hide

  • Novel targets for anti-angiogenic therapy, 

    2008.04
    -
    Present

  • Mechanisms for Neuro-vascular crosstalk, 

    2006.04
    -
    Present

  • Molecular mechanisms for angiogenesis, 

    2000.04
    -
    Present

 

Papers 【 Display / hide

  • A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis

    Kim Y., Choi J., Yang M., Hong S., Lee C., Kubota Y., Lim D., Koh G.

    Nature Communications (Nature Communications)  10 ( 1 )  2019.12

     View Summary

    © 2019, The Author(s). Hypoxia is a main driver of sprouting angiogenesis, but how tip endothelial cells are directed to hypoxic regions remains poorly understood. Here, we show that an endothelial MST1–FOXO1 cascade is essential for directional migration of tip cells towards hypoxic regions. In mice, endothelial‐specific deletion of either MST1 or FOXO1 leads to the loss of tip cell polarity and subsequent impairment of sprouting angiogenesis. Mechanistically, MST1 is activated by reactive oxygen species (ROS) produced in mitochondria in response to hypoxia, and activated MST1 promotes the nuclear import of FOXO1, thus augmenting its transcriptional regulation of polarity and migration‐associated genes. Furthermore, endothelial MST1‐FOXO1 cascade is required for revascularization and neovascularization in the oxygen-induced retinopathy model. Together, the results of our study delineate a crucial coupling between extracellular hypoxia and an intracellular ROS‐MST1‐FOXO1 cascade in establishing endothelial tip cell polarity during sprouting angiogenesis.

  • p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia

    Yokoyama M., Shimizu I., Nagasawa A., Yoshida Y., Katsuumi G., Wakasugi T., Hayashi Y., Ikegami R., Suda M., Ota Y., Okada S., Fruttiger M., Kobayashi Y., Tsuchida M., Kubota Y., Minamino T.

    Journal of Molecular and Cellular Cardiology (Journal of Molecular and Cellular Cardiology)  129   105 - 117 2019.04

    ISSN  00222828

     View Summary

    © 2019 Elsevier Ltd p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.

  • Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration

    Kim J., Park J., Choi J., Park I., Hwang Y., Bae H., Kim Y., Choi W., Yang J., Han S., Chung T., Kim P., Kubota Y., Augustin H., Oh W., Koh G.

    Science Advances (Science Advances)  5 ( 2 )  2019.02

     View Summary

    Copyright © 2019 The Authors. Choriocapillary loss is a major cause of neovascular age-related macular degeneration (NV-AMD). Although vascular endothelial growth factor (VEGF) blockade for NV-AMD has shown beneficial outcomes, unmet medical needs for patients refractory or tachyphylactic to anti-VEGF therapy exist. In addition, the treatment could exacerbate choriocapillary rarefaction, necessitating advanced treatment for fundamental recovery from NV-AMD. In this study, Tie2 activation by angiopoietin-2–binding and Tie2-activating antibody (ABTAA) presents a therapeutic strategy for NV-AMD. Conditional Tie2 deletion impeded choriocapillary maintenance, rendering eyes susceptible to NV-AMD development. Moreover, in a NV-AMD mouse model, ABTAA not only suppressed choroidal neovascularization (CNV) and vascular leakage but also regenerated the choriocapillaris and relieved hypoxia. Conversely, VEGF blockade degenerated the choriocapillaris and exacerbated hypoxia, although it suppressed CNV and vascular leakage. Together, we establish that angiopoietin-Tie2 signaling is critical for choriocapillary maintenance and that ABTAA represents an alternative, combinative therapeutic strategy for NV-AMD by alleviating anti-VEGF adverse effects.

  • TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity

    Naito H., Iba T., Wakabayashi T., Tai-Nagara I., Suehiro J., Jia W., Eino D., Sakimoto S., Muramatsu F., Kidoya H., Sakurai H., Satoh T., Akira S., Kubota Y., Takakura N.

    Developmental Cell (Developmental Cell)  48 ( 2 ) 151 - 166.e7 2019.01

    ISSN  15345807

     View Summary

    © 2018 Elsevier Inc. Mechanisms by which endothelial cells (ECs) maintain themselves in inflammatory microenvironments remain unclear. Naito et al. show that TAK1 prevents EC apoptosis induced by TNF-α-expressing myeloid cells. TAK1 protects ECs and ensures the maintenance of vascular integrity and homeostasis under inflammatory conditions.

  • Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction

    Lee S., Lee C., Kang S., Park I., Kim Y., Kim S., Hong S., Bae H., He Y., Kubota Y., Koh G.

    Journal of Clinical Investigation (Journal of Clinical Investigation)  128 ( 11 ) 5018 - 5033 2018.11

    ISSN  00219738

     View Summary

    © 2018 American Society for Clinical Investigation. All rights reserved. Emerging evidence indicates that angiopoietin-2 (Angpt2), a well-recognized vascular destabilizing factor, is a biomarker of poor outcome in ischemic heart disease. However, its precise role in postischemic cardiovascular remodeling is poorly understood. Here, we show that Angpt2 plays multifaceted roles in the exacerbation of cardiac hypoxia and inflammation after myocardial ischemia. Angpt2 was highly expressed in endothelial cells at the infarct border zone after myocardial infarction (MI) or ischemia/reperfusion injury in mice. In the acute phase of MI, endothelial-derived Angpt2 antagonized Angpt1/Tie2 signaling, which was greatly involved in pericyte detachment, vascular leakage, increased adhesion molecular expression, degradation of the glycocalyx and extracellular matrix, and enhanced neutrophil infiltration and hypoxia in the infarct border area. In the chronic remodeling phase after MI, endothelial- and macrophage-derived Angpt2 continuously promoted abnormal vascular remodeling and proinflammatory macrophage polarization through integrin α 5 β 1 signaling, worsening cardiac hypoxia and inflammation. Accordingly, inhibition of Angpt2 either by gene deletion or using an anti- Angpt2 blocking antibody substantially alleviated these pathological findings and ameliorated postischemic cardiovascular remodeling. Blockade of Angpt2 thus has potential as a therapeutic option for ischemic heart failure.

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Papers, etc., Registered in KOARA 【 Display / hide

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • Analysis for organ-specific vascular patterning

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 久保田 義顕, Grant-in-Aid for Scientific Research (B), Principal Investigator

  • Mechanisms for specification of blood and lymphatic vessels

    2018.06
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 久保田 義顕, Grant-in-Aid for Challenging Research (Exploratory) , Principal Investigator

  • Regulatory mechanisms of microglial activation and neuropsychiatric disorders

    2018.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 久保田 義顕, Grant-in-Aid for Scientific Research on Innovative Areas, Principal Investigator

  • Role of the VEGF/VEGFR2 signaling in vascular stability

    2015.04
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    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 久保田 義顕, Grant-in-Aid for Challenging Exploratory Research, Principal Investigator

     View Summary

    Blood vessels are distributed throughout the body during development. This developmental process depends on the signaling of vascular endothelial growth factor (VEGF) and its main receptor, VEGFR2. However, the precise role of VEGF on vascular endothelial cells, in particular the role in the maintenance of their stability is not clear. In this study, we generated tamoxifen-inducible endothelial VEGFR2 knockout mice (Cdh5-BAC-CreERT2+;Vegfr2flox./flox) and morphologically analyzed the retina of the mutant mice at a single cell level. We found not only abrogation of the formation of new vessels but also the striking regression of established ones. This phenotype was mostly recapitulated by neuron-specific VEGF knockout mice (Chx10-Cre+Vegfaflox/flox). Overall our study suggests that the VEGF/VEGFR2 signaling positively regulates the stability of established blood vessels.

  • Strategy to improve the quality of wound angiogenesis

    2013.04
    -
    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 久保田 義顕, Grant-in-Aid for Young Scientists (A), Principal Investigator

     View Summary

    Once skin tissues are injured, the endogenous healing program takes place and damaged tissues are repaired or regenerated. Angiogenesis, formation of new blood vessels from nascent vessels, are believed to play a central role in this repairing process. However, the entity of the kinetics of blood vessels associated with wound healing is only ambiguously clarified. Here we established a new wound healing model using neonatal mice, suitable for visualizing the 3-D structure of blood vessels in wound tissues. Utilizing this technique, we found vascular changes during wound repair are mainly the vascular enlargement accompanied by increased blood flow, and the vessel curving caused by wound contraction, rather than typical angiogenesis. We also found the increase in diameter and blood flow depends on the VEGF-VEGFR2 signaling. These results suggest the vascular remodeling during wound healing is not a typical angiogenesis, but uniquely characterized as enlargement and curving.

Awards 【 Display / hide

  • Keio Medical School Faculty and Alumni Grants

    Yoshiaki Kubota, 2013, Keio University

    Country: JAPAN

  • Young Investigator Okamoto Award

    Yoshiaki Kubota, 2013

    Country: JAPAN

  • Kao Research Encouragement Award

    Yoshiaki Kubota, 2013

    Country: JAPAN

  • Kitasato Award

    Yoshiaki Kubota, 2011, Keio University

    Country: JAPAN

  • Hematology/Vascular Research Orbis Young Investigator Award (1st Pzize)

    Yoshiaki Kubota, 2008

    Country: JAPAN

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Courses Taught 【 Display / hide

  • ANATOMY: PRACTICE

    2019

  • ANATOMY

    2019

  • ADVANCED DEVELOPMENTAL BIOLOGY

    2019

  • ADVANCED ANATOMY

    2019

  • ANATOMY: SEMINAR

    2019

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Courses Previously Taught 【 Display / hide

  • 横浜市立大学医学部 解剖学実習・講義

    Keio University, 2015, Full academic year, Major subject, Laboratory work/practical work/exercise

  • 医学部3年生 病理学教室講義 循環器の病理1「動脈硬化症・動脈瘤・血管の炎症」

    Keio University, 2015, Autumn Semester, Major subject, Lecture

  • 理工学部2015年度秋学期「再生・遺伝子の科学」

    Keio University, 2015, Autumn Semester, Major subject, Lecture

  • 医学研究科博士課程医学特別講義

    Keio University, 2015, Spring Semester, Lecture

  • 医学研究科修士課程分子病態学講義

    Keio University, 2015, Spring Semester, Major subject, Lecture

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