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Moleculo-pathological Study on the Homeostatic and Deregulated Mechanisms of Vascular Remodeling

血管重塑稳态和失调机制的分子病理学研究

基本信息

批准号：
16209012
负责人：
SUEISHI Katsuo
金额：
$ 30.78万
依托单位：
KYUSHU UNIVERCITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Major findings obtained in this project are as follows :1. Patho-physiological study on the pathological vascular remodeling1)Atherosclerosis and angiogenesis : Intimal neovascularization related to the function of not only VEGF-A, C and D expression but also PEDF in human coronary arteries and aortas were immunohistochemically examined and clarified to be equivalent to the histopathological hallmark of active atherogenesis, leading to the hypothesis that intimal neovascularization participates intimately in the progression of human atherosclerosis on the basis of "inflammation and repair process".2)Aortic atherosclerosis in apoE-/-mice was accelerated by VEGF-A and-C through VEGFR-1/2 and-2/3 heteromers, but not through single activation of VEGFR activated by VEGF-B/E and P1GF.3)Pathologically examining autopsy cases in Hisayama-Cohort Study, diabetes mellitus and chronic renal failure became evident to be an independent risk factor of coronary atherosclerosis.4)PKC activation and suppression of PDGF-B induced in STZ-induced diabetic animal models intimately corresponded to the both low resistance to tissue ischemia and insufficient angiogenesis/vasculogenesis.5)The positive interaction between VEGF-C and PDGF-B played an important role in the functional angiogenesis in ischemic tissues, in addition to the Ang-1/Tie-2/PDGF-B interaction. Moreover, FGF-2 function could enhance these positive loops, and thus can actively participate in the integrated angiogenesis.2. Exploitation of novel gene transfer vectors and their clinical applications1)Molecular and biological characteristics of SIV, particularly on ubiquitous cell targets and low frequency of insertional mutagenesis have been clarified.2)FGF-2-dFSeV and PEDG-SIV have been progressed to the clinical researches, namely, to human peripheral arterial disease (atherosclerosis obliterans and Buerger disease) and retinal degeneration, respectively.

主要研究结果如下：1.病理性血管重塑的病理生理学研究1）动脉粥样硬化和血管生成：血管内新血管形成不仅与VEGF-A、C和D表达的功能有关，而且与人冠状动脉和动脉粥样硬化中的PEDF的功能有关，经化学方法检查和澄清，其等同于活跃的动脉粥样硬化形成的组织病理学标志，从而提出内膜新生血管在“炎症和修复过程”的基础上密切参与人类动脉粥样硬化的发展的假设。2）apoE-/-小鼠被VEGF-A和-C通过VEGFR-1/2和-2/3异聚体加速，但不是通过VEGF-B/E和P1GF.3激活的VEGFR的单一激活。3）病理检查Hisayama队列研究中的尸检病例，糖尿病和慢性肾功能衰竭明显成为冠状动脉粥样硬化的独立危险因素。诱导的糖尿病动物模型密切对应于对组织缺血的低抵抗和血管生成/血管生成不足。5）除了Ang-1/Tie-2/PDGF-B相互作用之外，VEGF-C和PDGF-B之间的正相互作用在缺血组织中的功能性血管生成中起重要作用。而且FGF-2的功能可以增强这些阳性环，从而可以积极参与整合性血管生成.新型基因转移载体的开发及其临床应用1）SIV的分子生物学特性，特别是其广泛存在的细胞靶点和低频率的插入突变已被阐明。2）FGF-2-dFSeV和PEDG-SIV已进入临床研究，即分别应用于人类外周动脉疾病（动脉粥样硬化闭塞症和Buerger病）和视网膜变性。