MECHANISMS OF ARTERIAL GRAFT HEALING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 大约30%的血管介入（例如，移植物和支架）发生管腔狭窄，并且主要由于平滑肌细胞（SMC）生长、新生内膜增生和壁增厚而失败。虽然大多数研究都是针对预防新生内膜增生，但另一种选择可能是在管腔狭窄发生后刺激新生内膜萎缩。 我们已经证明，高血流量诱导狒狒PTFE移植物的新生内膜萎缩，但不是在正常髂动脉。此外，一个紧密的PTFE包裹在狒狒髂动脉周围会导致显著的壁萎缩。我们进行了DNA微阵列实验，以确定在两种模型（即移植物新生内膜和包裹动脉）萎缩过程中调控的基因，并发现了15个基因（9个增加和6个减少）。 其中，9个上调基因中的8个和6个下调基因中的3个通过定量RT-PCR验证。上调的基因包括细胞外基质降解因子ADAMTS 4、组织纤溶酶原激活物和透明质酸酶2。我们已经发现，使用FasL刺激细胞死亡增加了培养的平滑肌细胞中5个经验证的上调基因的表达，并降低了2个经验证的下调基因的表达，从而将这些基因与体内萎缩期间观察到的细胞死亡联系起来。进一步的实验正在进行中，以确定是否使用siRNA下调ADAMTS 4、组织纤溶酶原激活剂或透明质酸酶2将改变对体外FasL治疗的死亡反应。我们也将试图确定这些基因是否在狭窄的动脉粥样硬化的人颈动脉变薄的纤维帽中表达（或抑制）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Approximately 30% of vascular interventions (for example, grafts and stents) develop lumenal narrowing and fail largely as a result of smooth muscle cell (SMC) growth, neointimal hyperplasia, and wall thickening. While most research has been directed at preventing neointimal hyperplasia, an alternative might be to stimulate neointimal atrophy after lumenal narrowing has developed. We have demonstrated that high blood flow induces neointimal atrophy in baboon PTFE grafts, but not in the normal iliac artery. In addition, a tight PTFE wrap around the baboon iliac artery causes significant atrophy of the wall.We have conducted a DNA microarray experiment to identify genes that are regulated during atrophy in both models (i.e. graft neointima and wrapped artery) and have found 15 genes (9 increased and 6 decreased). Of these, 8 of 9 upregulated genes and 3 of 6 down-regulated genes were verified by quantitative RT-PCR. Upregulated genes included the extracellular matrix degrading factors ADAMTS4, tissue plasminogen activator, and hyaluronidase 2. We have found that stimulation of cell death using FasL increases the expression of 5 of the verified upregulated genes and decreases expression of 2 of the verified down-regulated genes in cultured smooth muscle cells, thus linking these genes to the cell death observed during atrophy in vivo. Further experiments are underway to determine if down-regulation of ADAMTS4, tissue plasminogen activator, or hyaluronidase 2 using siRNA will alter the death response to FasL treatment in vitro. We will also attempt to determine whether these genes are expressed (or repressed) in the thinning fibrous cap of stenotic atherosclerotic human carotid arteries.