MECHANISMS OF ARTERIAL GRAFT HEALING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 大约30%的血管介入治疗(例如移植物和支架)发展为管腔狭窄，主要原因是平滑肌细胞(SMC)生长、新生内膜增生和管壁增厚。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后刺激新生内膜萎缩。我们已经证明，高血流量会导致狒狒聚四氟乙烯移植物的新生内膜萎缩，但在正常的髂动脉中不会。此外，紧密的聚四氟乙烯包裹在狒狒的髂动脉上会导致动脉壁的显著萎缩。我们已经进行了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的动脉)萎缩过程中受到调控的基因，并发现了15个基因(9个增加，6个减少)。其中，9个上调基因中有8个基因表达上调，6个基因表达下调中有3个基因表达下调。上调的基因包括细胞外基质降解因子ADAMTS4、组织型纤溶酶原激活剂和透明质酸酶2。我们发现，在培养的平滑肌细胞中，用FasL刺激细胞死亡，5个上调基因的表达增加，2个下调基因的表达减少，从而将这些基因与体内萎缩过程中观察到的细胞死亡联系在一起。进一步的实验正在进行中，以确定使用siRNA下调ADAMTS4或组织纤溶酶原激活剂是否会改变体外对FasL治疗的死亡反应。我们还开始在一项人类静脉移植物SMC的研究中探索狒狒结果的含义，以检验这样一种假设，即移植物显著狭窄(25%的移植物)的变异性可以通过内源性细胞的过度增殖反应来解释，并且这一过程可能通过诱导细胞死亡和内膜萎缩来逆转。

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 or tissue plasminogen activator using siRNA will alter the death response to FasL treatment in vitro. We have also begun to explore the implications of the baboon results in an investigation of human vein graft SMCs to test the hypothesis that the variability in significant graft narrowing (25% of grafts) can be accounted for by a hyperproliferative response of the endogenous cells and that the process might be reversed by inducing cell death and intimal atrophy.