Roles of VEGF type 1 receptor signaling in pathologicalangiogenesis/lymphangiogenesis

VEGF 1 型受体信号传导在病理性血管生成/淋巴管生成中的作用

• 批准号: 21390072
• 负责人: MAJIMA Masataka
• 金额: $ 11.9万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390072/
• 关键词: 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; VEGFR-1シグナリング; 肺再生; 肺胞上皮細胞; VEGFR1チロシンキナーゼノックアウトマウス; 1型受容体; 肝修復; がん; 慢性炎症; 血小板; VEGF 1型受容体; アセトアミノフェン; 肝障害; 類洞; マクロファージ; 血管内皮細胞; 肝細胞; 血管内皮細胞増殖因子; tyrosin kinase

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.

血管内皮生长因子（VEGF）是一种重要的促血管生成因子。VEGF具有3种受体，即VEGFR 1（Flt-1）、VEGFR 2（Flk-1/KDR）和VEGFR 3（Flt-4）。我们以前曾报道过，精氨酸介导的SDF-1从血小板中释放的幅度和非内皮CXCR 4 + VEGFR 1+造血祖细胞（“血管细胞”）的募集构成了血管生成的主要决定因素。我们测试了Flt-1酪氨酸激酶（TK）信号通过刺激骨髓干细胞的干细胞因子（SCF）和MMP-9来增强血管生成。与WT相比，TKKO中的血流恢复显著延迟。与WT相比，SCF和pro-MMP 9的血浆浓度在TKKO中显著降低。在两种小鼠中VEGF的浓度之间没有显著差异，但是在TKKO中，血小板沉积的微血管密度被显著抑制。这些结果表明，Flt-1的信号传导对于从急性缺血性病症中恢复是必不可少的。应用选择性VEGFR 1激动剂治疗缺血性心脏病可能是一种新的治疗策略。

项目成果

Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers

• DOI: 10.1152/ajpgi.00013.2010
• 发表时间: 2010-11-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
• 影响因子: 4.5
• 作者: Ae, Takako;Ohno, Takashi;Majima, Masataka
• 通讯作者: Majima, Masataka

Heterogeniety of endothelial cells : Thromboxane-dependent platelet adhesion and angiogenesis

内皮细胞的异质性：血栓素依赖性血小板粘附和血管生成

• 发表时间: 2011
• 作者: 古川鋼一;大海雄介;田島織絵;大川祐樹;徳田典代;古川圭子;Majima M
• 通讯作者: Majima M

Estimating the contribution of genes to variation in renal drug clearance by active secretionusing multiple data from clinical phase I studies

使用临床 I 期研究的多个数据估计基因对主动分泌引起的肾脏药物清除率变化的贡献

• DOI: 10.1177/0091270009348502
• 发表时间: 2010
• 期刊: J Clin Pharmacol
• 影响因子: 2.9
• 作者: Fujita T;Kumagai Y;Nakahara I;Ohtani Y;Majima M
• 通讯作者: Majima M

EP3/EP4 signaling regulates tumor microenvironment formation by bone marrow-derived fibroblasts

• DOI: 10.2492/inflammregen.31.316
• 发表时间: 2011
• 期刊: Inflammation and Regeneration
• 影响因子: 8.1
• 作者: H. Katoh;K. Hosono;Tatsunori Suzuki;M. Watanabe;M. Majima

Effect of Erythropoietin on Angiogenesis With the Increased Adhesion of Platelets to the Microvessels in the Hind-Limb Ischemia Model in Mice

• DOI: 10.1254/jphs.09262fp
• 发表时间: 2010-02-01
• 期刊: JOURNAL OF PHARMACOLOGICAL SCIENCES
• 影响因子: 3.5
• 作者: Kato, Shintaro;Amano, Hideki;Majima, Masataka
• 通讯作者: Majima, Masataka