Pathophysiological Mechanisms of Angiogenesis-Related Diseases

本课题在2年的研究过程中，采用从细胞、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，主要研究结果如下：1.我们阐明了单核细胞/巨噬细胞趋化蛋白-1（MCP 1）在FGF-2介导的血管再生过程中的关键作用（发表于Arteriosclr Thromb Vasc Biol 2006）。2.我们发现了一个新的蛋白激酶-C（PKC）eta的单核苷酸多态性（SNP），与脑梗死密切相关（发表在Nature Genetics 2006）。3.我们发现在人类动脉粥样硬化的非常早期过程中，在巨噬细胞积聚之前，氧化脂质在内膜下层沉积（发表于Arteriosclr Thromb Vasc Biol 2006）。4.我们建立了内源性生长因子抑制剂的双敲除小鼠系，即Spred-1和Spred-2。该品系的小鼠在第13.5天表现出胚胎致死性，这是由VEGFR 3信号传导引起的淋巴管异常发育引起的（Mol Cell Biol 2007）。5. VEGRR 1的一种配体胎盘生长因子（PlGF）在FGF-2介导的血管生成过程中支持VEGF-A的功能（Atherovirus 2008）。6. FGF-2上调VEGF-C表达，形成与PDGF-BB表达相关的功能性毛细血管和淋巴管网络（投稿中）。7.他汀类药物通过一氧化氮（NO）/内皮型一氧化氮合酶（eNOS）而非PDGF-BB介导的毛细血管成熟来恢复糖尿病状态下的血管内皮功能，为动脉粥样硬化性疾病和代谢综合征的治疗提供了新的思路。

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.