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Pathophysiological Mechanisms of Angiogenesis-Related Diseases

血管生成相关疾病的病理生理机制

基本信息

批准号：
18390115
负责人：
YONEMITSU Yoshikazu
金额：
$ 10.77万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390115/
关键词：
Generation and Development of Blood vessels Generation of Lymphatic vessels Sendai Virus Vector MCP-1 FGF-2 PDGF-BB Spred PKC eta 血管新生動脈硬化間葉系細胞

项目摘要

During 2-years' research project, we performed integrated research approach, from cell, animal model, to human materials, to investigate the genetic, molecular, and pathophysiological mechanisms of angiogenesis-related diseases.Major findings obtained in this project were as follows; 1. We clarified the critical role of monocyte/macrophage chamoattractant protein-1 (MCP 1) during revascularization mediated by FGF-2 (published in Arteriosclr Thromb Vasc Biol 2006). 2. We identified a new single nucleotide polymorphism (SNP) of protein kinase-C (PKC) eta critically related to cerebral infarction (published in Nature Genetics 2006). 3. We discovered the deposition of oxidized lipids at subintimal layer prior to macrophage accumulation in very early process of human atherosclerosis (published in Arteriosclr Thromb Vasc Biol 2006). 4. We established a double knockout mouse line for endogenous growth factor inhibitors, namely Spred-1 and Spred-2. Mice of this line exhibited embryonic lethal at day 13.5, that were caused by abnormal development of lymphatic vessels due to VEGFR3 signaling (Mol Cell Biol 2007). 5. A ligand of VEGRR1, placental growth factor (PlGF), support the function of VEGF-A during FGF-2-mediated angiogenesis (Atherosclerosis 2008). 6. FGF-2 upregulates VEGF-C expression to form functional capillary and lymphatic network associated with PDGF-BB expression (manuscript under submission). 7. Statins restore vascular endothelial function under diabetic state nitric oxide (NO)/ endothelial NO syntase (eNOS), but not capillary maturation by PDGF-BB, is critical in this process.These findings should contribute the understanding of and new therapeutic approach to atherosclerotic diseases and metabolic syndrome.

在为期两年的研究项目中，我们采用了从细胞、动物模型到人体材料的综合研究方法，对血管生成相关疾病的遗传、分子和病理生理机制进行了研究。本项目的主要发现如下：1.阐明了单核/巨噬细胞结合蛋白-1(MCP-1)在成纤维细胞生长因子-2介导的血管重建中的关键作用(发表在《动脉血栓血管生物学》2006年版)。2.我们发现了一个新的与脑梗塞相关的蛋白激酶C(PKC)ETA的单核苷酸多态性(SNP)(发表在《自然遗传学》2006年版)。3.在动脉粥样硬化的早期阶段，我们发现在巨噬细胞聚集之前，氧化脂质在内膜下沉积(发表在Arteriosclr Thromb VASc Biol 2006上)。4.建立了内源性生长因子抑制因子Spred-1和Spred-2双基因敲除小鼠系。该品系的小鼠在13.5天表现出胚胎死亡，这是由于VEGFR3信号导致淋巴管异常发育引起的(Mol Cell Biol 2007)。5.胎盘生长因子(PlGF)是VEGRR1的一种配体，在成纤维细胞生长因子-2介导的血管生成过程中支持血管内皮生长因子-A的功能(动脉粥样硬化，2008)。6.成纤维细胞生长因子-2上调血管内皮生长因子-C的表达，形成与PDGF-BB表达相关的功能性毛细血管和淋巴网络(提交稿)。7.在糖尿病状态下，他汀类药物对血管内皮功能的恢复起关键作用的是一氧化氮(NO)/内皮型一氧化氮合酶(ENOS)，而不是PDGF-BB诱导的毛细血管成熟。这些发现将有助于对动脉粥样硬化性疾病和代谢综合征的认识和新的治疗方法。