Details of a Researcher - Kubota, Yoshiaki

Papers - Kubota, Yoshiaki

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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

© 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.

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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

© 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.

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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

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.

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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

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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

© 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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Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells

Si S., Nakajima-Takagi Y., Iga T., Tsuji M., Hou L., Oshima M., Koide S., Saraya A., Yamazaki S., Takubo K., Kubota Y., Minamino T., Iwama A.

Experimental Hematology (Experimental Hematology) 63 41 - 51.e1 2018.07

ISSN 0301472X

© 2018 Elsevier Ltd Hematopoietic stem cells (HSCs) are exposed to various insults such as genotoxic stress, inflammation, and infection, which have a direct effect. These insults deplete, cause a functional decline in, and promote HSC aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have reported previously that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect the bone marrow (BM) vascular niche. Here, we demonstrate that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatments. The conditional activation of p53 in VE-cadherin+ vascular niche cells by deleting Mdm2 induces the expression of p53 target genes specifically in vascular endothelial cells, resulting in the dilation and collapse of vascular endothelial cells and reductions in perivascular mesenchymal stromal cell numbers. Consequently, hematopoietic stem cells (HSCs) fail to maintain dormancy, mobilize to the periphery, and are depleted significantly. Our results indicate that various hematopoietic insults affect HSCs, not only directly, but also indirectly by altering vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs.

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Distinct expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after myocardial infarction

Kurotsu S., Osakabe R., Isomi M., Tamura F., Sadahiro T., Muraoka N., Kojima H., Haginiwa S., Tani H., Nara K., Kubota Y., Ema M., Fukuda K., Suzuki T., Ieda M.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 495 ( 1 ) 884 - 891 2018.01

ISSN 0006291X

© 2017 Elsevier Inc. The coronary vascular system is critical for myocardial growth and cardiomyocyte survival. However, the molecular mechanism regulating coronary angiogenesis remains elusive. Vascular endothelial growth factor (VEGF) regulates angiogenesis by binding to the specific receptors Flk1 and Flt1, which results in different functions. Despite the importance of Flk1 and Flt1, their expression in the coronary vasculature remains largely unknown due to the lack of appropriate antibodies for immunostaining. Here, we analyzed multiple reporter mice including Flk1-GFP BAC transgenic (Tg), Flk1-LacZ knock-in, Flt1-DsRed BAC Tg, and Flk1-GFP/Flt1-DsRed double Tg animals to determine expression patterns in mouse hearts during cardiac growth and after myocardial infarction (MI). We found that Flk1 was expressed in endothelial cells (ECs) with a pattern of epicardial-to-endocardial transmural gradients in the neonatal mouse ventricle, which was downregulated in adult coronary vessels with development. In contrast, Flt1 was homogeneously expressed in the ECs of neonatal mouse hearts and expression was maintained until adulthood. After MI, expression of both Flk1 and Flt1 was induced in the regenerating coronary vessels at day 7. Intriguingly, Flk1 expression was downregulated thereafter, whereas Flt1 expression was maintained in the newly formed coronary vessels until 30 days post-MI, recapitulating their expression kinetics during development. This is the first report demonstrating the spatiotemporal expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after MI; thus, this study suggests that these factors have distinct and important functions in coronary angiogenesis.

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Plastic roles of pericytes in the blood-retinal barrier

Park DY, Lee J, Kim J, Kim K, Hong S, Han S, Kubota Yoshiaki, Augustin HG, Ding L, Kim JW, Kim H, He Y, Adams RH, *Koh GY.

Nat Commun 8 15296 - 15296 2017

Research paper (scientific journal), Accepted

VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis.

Jang JY, Choi SY, Park I, Park DY, Choe K, Kim P, Kim YK, Lee BJ, Hirashima M, Kubota Yoshiaki,Park JW, Cheng SY, Nagy A, Park YJ, Alitalo K, Shong M, *Koh GY.

EMBO Mol Med 9 ( 6 ) 750 - 769 2017