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Basic Research for Complex Molecular Mechanisms of the Process of the Functional Angiogenesis : toward the development of technologies controlling the molecular target of pathological angiogenesis.

功能性血管生成过程的复杂分子机制的基础研究：开发控制病理性血管生成分子靶标的技术。

基本信息

批准号：
16390118
负责人：
YONEMITSU Yoshikazu
金额：
$ 9.54万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Aim-To make it clear that molecular and cellular mechanisms of physiological and pathophysiological process of angiogenesis, we focused molecular networks among vascular cells (endothelial cells, mural cells, and mesenchymal cells) in view of FGF-2-mediated angiogenic process.Results-1.Using tissue samples of human coronary arteries, we revealed that frequency of an angiogenic/lymphangiogenic factor, VEGF-C corresponded to the AHA grade of athrosclerosis ; however, lymphangiogenesis was a rare event, indicating that VEGF-C functioned as an angiogenic factor rather than a lymphangiogenic factor (published in Human Pathology 2005).2.Using tissue samples of human coronary arteries, we demonstrated that deposition of an antiangiogenic factor, PEDF, was seen as patchy distribution, and negatively correlated to the frequency of intimal angiogenesis (published in Arterioscler Thromb Vasc Biol 2005).3.We showed that PDGF-AA/PDGFRa system, which was previously demonstrated as a controller of VEGF expression in mesenchymal cells (published in Circulation Research 2004), was an essential regulator of VEGF in non-small cell lung cancer as an angiogenic switch (published in Cancer Research 2005).4.The primary abnormality of diabetic microangiopathy was shown as a disease of disturbance of PDGF-BB/PKC axis but not of impaired expression of angiogenic factors (published in Circulation Research 2006).5.We demonstrated that FGF-2 stimulated an lymphangiogenic factor VEGF-C inducing not only lymphangiogenesis, but also capillary stabilization via upregulation of PDGF-BB (submitted).6.FGF-2 stimulates the expression of an inflammatory/arteriogenic chemokine, MCP-1,contributing functional angiogenesis (submitted).Conclusion-These findings reveals the molecular mechanisms of functional and pathological angiogenesis in various human diseases, and suggest the possible molecular targets both of angiogenic and antiangiogenic therapies.

目的：为了阐明血管生成生理和病理过程的分子和细胞机制，我们对血管细胞间的分子网络进行了研究结果：1.使用人冠状动脉的组织样本，我们揭示了血管生成/淋巴管生成因子的频率，VEGF-C与AHA分级相对应;然而，淋巴管生成是罕见的事件，表明VEGF-C作为血管生成因子而不是淋巴管生成因子发挥作用（发表在《人类病理学》2005年）。2.使用人类冠状动脉的组织样本，我们证明了抗血管生成因子PEDF的沉积，呈斑片状分布，与内膜血管生成频率呈负相关（发表于ArteriosclerThrombVascBiol 2005）。3.我们发现PDGF-AA/PDGFRa系统，其先前被证明是间充质细胞中VEGF表达的控制者，（发表于2004年《循环研究》），是非小细胞肺癌中VEGF作为血管生成开关的重要调节因子糖尿病微血管病变主要表现为PDGF-BB/PKC轴紊乱，而非血管生成因子表达受损我们证明FGF-2刺激淋巴管生成因子VEGF-C，不仅诱导淋巴管生成，而且通过上调PDGF-BB诱导毛细血管稳定6.FGF-2刺激炎症/动脉生成趋化因子MCP-1的表达，促进功能性血管生成结论-这些发现揭示了各种人类疾病中功能性和病理性血管生成的分子机制，并提出了血管生成和抗血管生成治疗的可能分子靶点。