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.

目的：为了明确血管生成生理和病理生理过程的分子和细胞机制，我们针对fgf -2介导的血管生成过程，重点研究血管细胞（内皮细胞、壁细胞和间充质细胞）之间的分子网络。利用人类冠状动脉的组织样本，我们发现血管生成/淋巴管生成因子VEGF-C的频率与动脉粥样硬化的AHA级别相对应；然而，淋巴管生成是一个罕见的事件，这表明VEGF-C的功能是血管生成因子而不是淋巴管生成因子（发表在Human Pathology 2005）。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，并且与内膜血管生成的频率呈负相关（发表在动脉粥样硬化血栓血管生物学2005年）。我们发现PDGF-AA/PDGFRa系统，之前被证明是间充质细胞中VEGF表达的控制者（发表在Circulation Research 2004），是非小细胞肺癌中VEGF的重要调节因子，作为血管生成开关（发表在cancer Research 2005）。糖尿病微血管病变的原发性异常表现为PDGF-BB/PKC轴紊乱，而非血管生成因子表达受损（发表于Circulation Research 2006）。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，还通过上调PDGF-BB诱导毛细血管稳定（提交）。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（提交）。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，并提示了血管生成和抗血管生成治疗可能的分子靶点。

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.