Roles of VEGF type 1 receptor signaling in pathologicalangiogenesis/lymphangiogenesis

2012 Fiscal Year Final Research Report

• Project/Area Number: 21390072
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kitasato University
• Principal Investigator: MAJIMA Masataka 北里大学, 医学部, 教授 (70181641)
• Co-Investigator(Kenkyū-buntansha): FUJITA Tomoe 北里大学, 医学部, 講師 (20296510) ; KAWAMURA Michiko 北里大学, 医学部, 助教 (00154104) ; AMANO Hideki 北里大学, 医学部, 講師 (60296481) ; SUZUKI Tatsunori 北里大学, 医学部, 助教 (70406940) ; KITASATO Hidero 北里大学, 医療衛生学部, 教授 (90195256)
• Project Period (FY): 2009 – 2012
• Keywords: 血管新生 / リンパ管新生 / VEGF / 1 型受容体 / ノックアウトマウス / 病態モデル / Gene targeting / 骨髄由来細胞

Research Abstract

Vascular endothelial growth factor (VEGF) is known as a major propangiogenic factor. VEGF has 3 receptors, namely VEGFR1 (Flt-1), VEGFR2 (Flk-1/KDR) and VEGFR3 (Flt-4). We had previously reported that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, ‘hemangiocytes,’ constitute the major determinant of angiogenesis. We tested that Flt-1 Tyrosine Kinase (TK) signaling enhances angiogenesisby stimulating Stem Cell Factor (SCF) and MMP-9 by bone marrow stem cells. Blood flow recovery in TKKO was significantly delayed compared to WT. Compared to WT, plasma concentrations of SCF and pro-MMP9 were significantly reduced in TKKO. There was no significant difference between the concentrations of VEGF in both mice, but in TKKO, platelets-deposited microvascular density was significantly suppressed. These results suggested that the signaling of the Flt-1 is essential for recovering from acute ischemic conditions. Administration of selective VEGFR1 agonist may be useful to treat the ischemia, and may become a novel therapeutic strategy in regenerative cardiovascular medicine.

Research Products

• [Journal Article] Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment (2013)
  • Author(s): Ohkubo H, Ito Y, Minamino T, Mishima T, Hirata M, Hosono K, Shibuya M, Yokomizo T, Shimizu T, Watanabe M, Majima M
  • Journal Title: FASEB J
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1A receptor signaling facilitates tumor metastasis formation through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells (2013)
  • Author(s): Amano H, Ito Y, Ogawa F, Eshima K, Suzuki T, Oba K, Matsui Y, Kato S, Fukui T, Nakamura M, Kitasato H, Fukamizu A, Majima M
  • Journal Title: Am J Pathol Volume: 182(2) Pages: 553-64
  • DOI: DOI:10.1016/j.ajpath.2012.10.026
  • Peer Reviewed
• [Journal Article] Tumor apoptosis in prostate cancer by PGD(2) and its metabolite 15d-PGJ(2) in murine model (2012)
  • Author(s): Nakamura M, Tsumura H, Satoh T, Matsumoto K, Maruyama H, Majima M, Kitasato H
  • Journal Title: Biomed Pharmacother Volume: 67(1) Pages: 66-71
  • DOI: DOI:10.1016/j.biopha.2012.10.012.
  • Peer Reviewed
• [Journal Article] Thromboxane A_2 receptor signaling facilitates tumor colonization through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells (2012)
  • Author(s): Matsui Y, Amano H, Ito Y, Eshima K, Suzuki T, Ogawa F, Iyoda A, Satoh Y, Kato S, Nakamura M, Kitasato H, Narumiya S, Majima M
  • Journal Title: Cancer Sci Volume: 103(4) Pages: 700-7
  • DOI: DOI:10.1111/j.1349-7006.2012.02200.x.
  • Peer Reviewed
• [Journal Article] Thromboxane A(2) receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment (2012)
  • Author(s): Minamino T, Ito Y, Ohkubo H, Hosono K, Suzuki T, Sato T, Ae T, Shibuya A, Sakagami H, Narumiya S, Koizumi W, Majima M
  • Journal Title: Toxicol Appl Pharmacol Volume: 259(1) Pages: 104-14
  • DOI: DOI:10.1016/j.taap.2011.12.013
  • Peer Reviewed
• [Journal Article] In vivo kinetics of indoxyl sulfate in humans and its renal interaction with angiotensin-converting enzyme inhibitor quinapril in rats (2011)
  • Author(s): Fujita T, Ishihara K, Yasuda S, Nakamura T, Maeda M, Kobayashi M, Sahashi K, Ikeda Y, Kumagai Y, Majima M
  • Journal Title: J Pharmacol Exp Ther Volume: 341(3) Pages: 626-33
  • DOI: DOI:10.1124/jpet.111.187732
  • Peer Reviewed
• [Journal Article] Application of a heatand steam-generating sheet increases peripheral blood flow and induces parasympathetic predominance (2011)
  • Author(s): Nagashima Y, Igaki M, Suzuki A, Tsuchiya S, Yamazaki Y, Hishinuma M,Oh-Ishi S, Majima M
  • Journal Title: Evid Based Complement Alternat Med Volume: 2011 Pages: 965095
  • DOI: DOI:10.1155/2011/965095
  • Peer Reviewed
• [Journal Article] Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema (2011)
  • Author(s): Kashiwagi S, Hosono K, Suzuki T, Takeda A, Uchinuma E, Majima M
  • Journal Title: Lab Invest Volume: 91(9) Pages: 1314-25
  • Peer Reviewed
• [Journal Article] Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation (2011)
  • Author(s): Hosono K, Suzuki T, Tamaki H, Sakagami H, Hayashi I, Narumiya S, Alitalo K, Majima M
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(5) Pages: 1049-58
  • DOI: DOI:10.1161/ATVBAHA.110.222356.
  • Peer Reviewed
• [Journal Article] Microsomal prostaglandin E synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice (2011)
  • Author(s): Isono M, Suzuki T, Hosono K, Hayashi I, Sakagami H, Uematsu S, Akira S, DeClerck YA, Okamoto H, Majima M
  • Journal Title: Life Sci Volume: 88(15-16) Pages: 693-700
  • DOI: DOI:10.1016/j.lfs.2011.02.008
  • Peer Reviewed
• [Journal Article] Vascular endothelial growth factor receptor-1 signalingpromotes liver repair through restoration of liver microvasculature afteracetaminophen hepatotoxicity (2011)
  • Author(s): Kato T, Ito Y, Hosono K, Suzuki T, Tamaki H, Minamino T, Kato S, Sakagami H, Shibuya M, Majima M
  • Journal Title: Toxicol Sci Volume: 120(1) Pages: 218-29
  • DOI: DOI:10.1093/toxsci/kfq366.
  • Peer Reviewed
• [Journal Article] The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model (2011)
  • Author(s): Numao A, Hosono K, Suzuki T, Hayashi I, Uematsu S, Akira S, Ogino Y, Kawauchi H, Unno N, Majima M
  • Journal Title: Biomed Pharmacother Volume: 65(1) Pages: 77-84
  • DOI: DOI:10.1016/j.biopha.2010.12.008
  • Peer Reviewed
• [Journal Article] Calcitoningene-related peptide facilitates revascularization during hindlimb ischemia in mice (2011)
  • Author(s): Mishima T, Ito Y, Hosono K, Tamura Y, Uchida Y, Hirata M, Suzsuki T, Amano H, Kato S, Kurihara Y, Kurihara H, Hayashi I, Watanabe M, Majima M
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 300(2) Pages: H431-9
  • DOI: DOI:10.1152/ajpheart.00466.2010
  • Peer Reviewed
• [Journal Article] Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying (2010)
  • Author(s): Mizuguchi S, Ohno T, Hattori Y, Ae T, Minamino T, Satoh T, Arai K, Saeki T, Hayashi I, Sugimoto Y, Narumiya S, Saigenji K, Majima M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 299(5) Pages: G1078-86
  • DOI: DOI:10.1152/ajpgi.00524.2009.
  • Peer Reviewed
• [Journal Article] Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers (2010)
  • Author(s): Ae T, Ohno T, Hattori Y, Suzuki T, Hosono K, Minamino T, Sato T, Uematsu S, Akira S, Koizumi W, Majima M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 299(5) Pages: G1139-46
  • DOI: DOI:10.1152/ajpgi.00013.2010.
  • Peer Reviewed
• [Journal Article] mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice (2010)
  • Author(s): Kamata H, Hosono K, Suzuki T, Ogawa Y, Kubo H, Katoh H, Ito Y, Uematsu S, Akira S, Watanabe M, Majima M
  • Journal Title: Biomed Pharmacother Volume: 64(6) Pages: 409-16
  • DOI: DOI:10.1016/j.biopha.2010.01.017.
  • Peer Reviewed
• [Journal Article] Effect of erythropoietin on angiogenesis with the increased adhesion of platelets to the microvessels in the hind-limb ischemia model in mice (2010)
  • Author(s): Kato S, Amano H, Ito Y, Eshima K, Aoyama N, Tamaki H, Sakagami H, Satoh Y, Izumi T, Majima M
  • Journal Title: J Pharmacol Sci Volume: 112(2) Pages: 167-75
  • Peer Reviewed
• [Journal Article] COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems (2010)
  • Author(s): Katoh H, Hosono K, Ito Y, Suzuki T, Ogawa Y, Kubo H, Kamata H, Mishima T, Tamaki H, Sakagami H, Sugimoto Y, Narumiya S, Watanabe M, Majima M
  • Journal Title: Am J Pathol Volume: 176(3) Pages: 1469-83
  • DOI: DOI:10.2353/ajpath.2010.090607.
  • Peer Reviewed
• [Journal Article] Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis (2010)
  • Author(s): Kubo H, Hosono K, Suzuki T, Ogawa Y,Kato H, Kamata H, Ito Y, Amano H, Kato T, Sakagami H, Hayashi I, Sugimoto Y, Narumiya S, Watanabe M, Majima M
  • Journal Title: Biomed Pharmacother Volume: 64(2) Pages: 101-6
  • DOI: DOI:10.1016/j.biopha.2009.04.039
  • Peer Reviewed
• [Journal Article] Recruited bone marrow cells expressing the EP3 prostaglandin E receptor subtype enhance angiogenesis during chronic inflammation (2010)
  • Author(s): Ueno T, Suzuki T, Oikawa A, Hosono K, Kosaka Y, Amano H, Kitasato H, Toda M, Hayashi I, Kato T, Ito Y, Sugimoto Y, Narumiya S, Okamoto H, Majima M
  • Journal Title: Biomed Pharmacother Volume: 64(2) Pages: 93-100
  • DOI: DOI:10.1016/j.biopha.2009.04.034
  • Peer Reviewed
• [Journal Article] Estimating the contribution of genes to variation in renal drug clearance by active secretionusing multiple data from clinical phase I studies (2010)
  • Author(s): Fujita T, Kumagai Y, Nakahara I, Ohtani Y, Majima M
  • Journal Title: J Clin Pharmacol Volume: 50(1) Pages: 109-14
  • DOI: DOI:10.1177/0091270009348502.
  • Peer Reviewed
• [Journal Article] Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis (2009)
  • Author(s): Kamei D, Murakami M, Sasaki Y, Nakatani Y, Majima M, Ishikawa Y, Ishii T, Uematsu S, Akira S, Hara S, Kudo I
  • Journal Title: Biochem J Volume: 425(2) Pages: 361-71
  • DOI: DOI:10.1042/BJ20090045
  • Peer Reviewed
• [Journal Article] Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis (2009)
  • Author(s): Amano H, Ito Y, Suzuki T, Kato S, Matsui Y, Ogawa F, Murata T, Sugimoto Y, Senior R, Kitasato H, Hayashi I, Satoh Y, Narumiya S, Majima M
  • Journal Title: Cancer Sci Volume: 100(12) Pages: 2318-24
  • DOI: DOI:10.1111/j.1349-7006.2009.01322.x.
  • Peer Reviewed
• [Journal Article] Reduced angiogenesis and delay in wound healing in angiotensin II type1a receptor-deficient mice (2009)
  • Author(s): Kurosaka M, Suzuki T, Hosono K, Kamata Y, Fukamizu A, Kitasato H, Fujita Y, Majima M
  • Journal Title: Biomed Pharmacother Volume: 63(9) Pages: 627-34
  • DOI: DOI:10.1016/j.biopha.2009.01.001.
  • Peer Reviewed
• [Journal Article] Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth (2009)
  • Author(s): Ogawa Y, Suzuki T, Oikawa A, Hosono K, Kubo H, Amano H, Ito Y, Kitasato H, Hayashi I, Kato T, Sugimoto Y, Narumiya S, Watanabe M. Majima M
  • Journal Title: Biochem Biophys Res Commun Volume: 382(4) Pages: 720-5
  • DOI: DOI:10.1016/j.bbrc.2009.03.094
  • Peer Reviewed
• [Journal Article] An ATP-sensitive potassium channel blocker suppresses sodium-induced hypertension through increased secretion of urinary kallikrein (2009)
  • Author(s): Kamata Y, Fujita T, Kato T, Hayashi I, Kurosaka M, Katori M, Fujita Y, Majima M
  • Journal Title: Hypertens Res Volume: 32(3) Pages: 220-6
  • DOI: DOI:10.1038/hr.2008.33.
• [Presentation] Roles of prostanoid receptor signaling in enhancement of tumor metastasis (2013)
  • Author(s): Ogawa F. Amano H. Majima M
  • Organizer: 86th Jap Pharmacological Society Annual Meeting
  • Place of Presentation: 福岡、日本
  • Year and Date: 2013-03-21
• [Presentation] 病態時の脈管新生を制御する脂質メディエーターの役割 (2012)
  • Author(s): Majima M
  • Organizer: 千里ライフサイエンスセミナー D5 脂質メディエーターと疾患
  • Place of Presentation: 大阪、日本
  • Year and Date: 2012-11-15
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis in diseases (2012)
  • Author(s): Majima M
  • Organizer: 第33回日本炎症・再生学会(シンポジウム)
  • Place of Presentation: 福岡、日本
  • Year and Date: 2012-07-06
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis (2012)
  • Author(s): Majima M
  • Organizer: 国際シンポジウム「1st International Symposium on Lipid Mediators」
  • Place of Presentation: 福岡, 日本
  • Year and Date: 2012-06-07
• [Presentation] Roles of thromboxane receptor signaling in enhancement of angiogenesis (2012)
  • Author(s): Majima M
  • Organizer: 17th International Vascular Biology Meeting (IVBM) 2012
  • Place of Presentation: Wiesbaden, Germany
  • Year and Date: 2012-06-03
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis during the developments of cancers and inflammation (2012)
  • Author(s): Majima M
  • Organizer: Keystone Symposium: Inflammation during Carcinogenesis
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2012-05-23
• [Presentation] Calcitonin Gene-related Peptide (2012)
  • Author(s): Majima M
  • Organizer: A neuronal cue for angiogenesisPacific Symposium on Vascular Biology in KAIST
  • Place of Presentation: Daejeon、Korea
  • Year and Date: 2012-04-26
• [Presentation] Roles of prostaglandins in enhancement of lymphangiogenesis in pathological states (2012)
  • Author(s): Majima M
  • Organizer: 85th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: Kyoto, 日本
  • Year and Date: 2012-03-14
• [Presentation] Prostanoids; Regulators of Pathological Lymphangiogenesis (2012)
  • Author(s): Majima M
  • Organizer: Gordon Research Conference: Molecular Mechanisms in Lymphatic Functions & Disease
  • Place of Presentation: Ventura, USA
  • Year and Date: 2012-03-07
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis in pathological conditions (2012)
  • Author(s): Majima M
  • Organizer: 89th Annual Meeting of The Physiological Society of Japan
  • Place of Presentation: 松本、日本
  • Year and Date: 2012-03-03
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis in pathological conditions (2012)
  • Author(s): Majima M
  • Organizer: Keystone Symposium: Angiogenesis
  • Place of Presentation: Snowbird, USA
  • Year and Date: 2012-01-10
• [Book] 「最新生理活性脂質研究-実験手法、基礎的知識とその応用-」遺伝子医学 MOOK 24 号 (2013)
  • Author(s): 馬嶋正隆
  • Publisher: メディカル ドゥ社(印刷中)
• [Book] 標準薬理学第7版 (2013)
  • Author(s): 馬嶋正隆
  • Publisher: 医学書院(印刷中)
• [Remarks] 研究室ホームページ
  • URL: http://www.med.kitasato-u.ac.jp/pharm/