Recovery from the Impaired Microvascular Neovascularization in Failung Myocardium

本研究的目的是在衰竭心肌重构过程中，心肌血流中血管生成导致毛细血管微血管异常，心功能进一步恶化的假设机制下，阐明血管生成治疗的有效性。观察到扩张型心肌病模型仓鼠血管内皮生长因子的基因表达和小静脉毛细血管密度与心肌模型仓鼠相同恢复，心肌细胞密度在心功能不全阶段下降，毛细血管密度下降，纤颤组织体积增加，抑制血管内皮生长因子的基因表达，药物治疗抑制心肌纤维。计划在1999财年，我们以VEGF为靶点，将人类血管生成素1和2基因引入心肌。到目前为止，腺病毒一直被认为是一种异物，这是一个问题。为了抑制T细胞的共刺激信号，制备了AdexCTLA4Ig，并开发了诱导免疫耐受条件的技术。已制备Adex CTLA4Ig，证实LacZ广泛表达。内皮细胞的血管生成是由VEGF诱导的，而血管生成素1和控制因子血管生成素2对其进行调节。目前，其使用的VEGF、血管生成素1、血管生成素2单基因或基因导入均在试验中。此外，由于传统方法难以捕捉血管结构的变化，因此正在对同步辐射SPring8与新生儿血管的微血管构建进行分析。虽然在做出决定之前还有几个步骤需要克服，但这些复杂的研究为分子心脏病学领域提供了原始和重要的发现。

The aim of this research project was to clarify whether it establishes the usefulness of the angiogenesis therapy on the assumption of the mechanism that in remodeling process of the failing myocardium, abnormalities in the capillary microvasculature by the angiogenesis develops in myocardial blood flow and that the cardiac function deteriorates further in the failing heart. It was observed that gene expression and venule capillary density of VEGF recovered with that in dilated cardiomyopathy model hamster, the myocardial cell density decreases for a cardiac insufficiency stage, and that the capillary density decreases, while the fibrillation organization volume increases, and that it suppresses the gene expression of VEGF, that and, it suppresses the myocardial fiber by the pharmacotherapy. It was planned that 1999 fiscal year, we introduced human angiopoietin 1 and 2 genes to the heart muscle with VEGF as a gene as a target. Until now, there was a problem that adenovirus, which was recognized as a foreign body. In order to suppress costimulatory signal of a T cell, AdexCTLA4Ig was produced, and the technique which induced the immunologic tolerance condition was developed. Already Adex CTLA4Ig was made, and the extensive expression of LacZ was confirmed. The endothelial cell is induced the angiogenesis by VEGF, and activating factor angiopoietin 1 and control factor angiopoietin 2 adjust it. At present, VEGF, angiopoietin 1 , angiopoietin 2 single or gene introduction it uses are being tried 2 each. And, microvasculature construction using synchrotron radiation SPring8 with the newborn blood vessel is being analyzed, since to catch the change of the angioarchitecture in the conventional method is difficult. Altough ther remain several steps to be overcome before making decision, these sophisticated studies provide original and important findings in the field of molecular cardiology.