Significantly heightened inflammatory responses detected in both EC and SMC at 12 and 24 H suggested a central role for inflammation in driving the Cinoxacin injury response to vein graft implantation. By 7 D, inflammation related genes tapered down without returning to basal levels. In fact, inflammatory genes spanned all time-points, were the most abundant of differentially regulated genes, and were likely the key regulators of other pathogenic processes. We propose that early targeting of key inflammatory molecules could be an ideal approach to prevent vein graft implantation injury. Previous in vivo studies have demonstrated that blocking inflammatory responses do attenuate IH. Following heightened inflammation driven injury response, we observed at later time-points, a significant upregulation of cell cycle related genes in both EC and SMC. Recovery of the endothelium through cell proliferation is beneficial to the healing process, while that of SMC may be deleterious, as it promotes the development of a neointimal layer, i.e. IH, the pathognomonic feature of mid-term vein graft failure. Accordingly, therapies aimed at preventing/treating vein graft failure using cell cycle inhibitors must spare EC, specifically target SMC, and ideally be effective for at least a week following vein graft implantation. Failure of the PREVENT trial may be related to the therapeutic agent not fulfilling all of these criteria. Genes involved in the extracellular matrix reorganization were significantly up-regulated by 30 D in both EC and SMC. In particular, collagen genes were the most enriched class of ECM components, consistent with the prominence of collagen as a constituent of IH lesion. Deposition of ECM is essential for vein graft healing in response to injury under normal circumstances, however in the special case of implantation injury it can lead to Mechlorethamine hydrochloride stenosis and graft failure. Delayed therapies that could tackle ECM deposition need to be optimized for reducing pathogenic vascular remodeling while promoting positive vascular remodeling. In order to delineate a causality relationship between differentially expressed genes after vein graft implantation, we analyzed the data using a backpropagation approach that integrates interactions between differentially expressed genes from the different points, starting at the latest time-point; i.e. 30 D. This means of analyzing the data offered a unique perspective of identifying the upstream pathogenic effectors of vein graft implantation injury, based on endpoint molecular signals involved in lesion formation. Furthermore, this approach allowed us to integrate into the same network genes derived from significantly affected biological pathways and define interconnectivity between these pathways. We identified 6 and 5 biological pathways that were dominant in the backpropagation networks of EC and SMC, respectively. Remarkably 4 of these pathways were common to both cell types, three of which spanned all time-points, namely the IL-8, IL-6 and dendritic cell maturation pathways. We surmise that these 3 pathways are not only critical pathogenic effectors of 
vein graft implantation injury, but also harbor promising therapeutic targets. Within these pathways, the IL-8 gene itself was up-regulated from 2 H to 7 D in EC and from 12 H to 7 D in SMC, and the IL-6 gene was up-regulated from 12 H to 7 D in both EC and SMC. We propose that both IL-8 and IL-6 are central to the pathogenesis of vein graft implantation injury. Specifically, IL-8 is a pro-inflammatory CXC chemokine produced mainly by neutrophils, monocytes and macrophages.