MECHANISMS OF ARTERIAL GRAFT HEALING

University Of Washington, Seattle WA

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Abstract

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 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.