**4. The graft "environment" at a cellular level**

The vascular endothelium has many protective functions, and it releases factors that maintain vein graft patency. The endothelium serves as the physical barrier between the blood compo‐ nents and the sub-endothelium, damage to this endothelium by either direct or indirect stress can disrupt this protective environment causing the formation of atheromas and subsequently graft failure. Injury to the endothelium in addition to surgical manipulation also increases the risk for vasospasm, stenosis, and intimal hyperplasia. Studies have shown that many factors can affect the viability of endothelium; these include temperature, distention, and the compo‐ sition of solution used in vein preparation. Nitric oxide controls vascular tone in addition to causing vasodilatation. Vascular endothelium contains L-arginine which when combined with nitric oxide synthase forms nitric oxide1 . The main target of nitric oxide is to stimulate guanylate cyclase and subsequently form guanosine 3 prime 5 prime-cyclic monophosphate (cGMP). The cGMP leads to vasodilatation and inhibition of platelet aggregation [19]. Fur‐ thermore, nitric oxide also has been shown to interfere with cell migration, specifically white cells by reducing the adhesion of neutrophils to the endothelial surface. Several cytoprotective properties are conferred through nitric oxide including; scavenging of oxygen free radicals and blocking release of prostaglandin E2 and F2 alpha. These are anti-inflammatory effects, and are quite intricate in detail, but are based on regulation of transcription factors [20], [21]. Nitric oxide also has some cytotoxic effects including decreasing protein synthesis, increasing lipid peroxidation, and decreasing acute phase proteins [22]. Injury to the endothelium directly causes a decrease in nitric oxide release by the endothelial cells and destroys the integrity of the vein. Studies performed by Kown et al. showed that vein grafts treated with L-arginine (nitric oxide is a by-product created when L-arginine is converted to citrulline) can increase levels of nitric oxide and subsequently decrease hyperplasia [23].

**6. The role of neointimal hyperplasia in graft patency**

of the vein conduit by as much as 25%.

onment within the saphenous vein.

Neointimal hyperplasia is the accumulation of smooth muscle cells and extracellular matrix that occurs in the intimal layer of vein. This thickening leads to a narrowing of the lumen and subsequent stenosis of the vein graft. Neointimal hyperplasia is the most widely accepted reason for graft failure at the present time. Many theories exist as to why this occurs but none have been completely proven. Work is currently being performed evaluating the up regulation of genes or proteins that may cause the phenomenon of intimal hyperplasia [15]. Nearly all vein grafts placed into an arterial system develop some areas of hyperplasia within the first four weeks. This acute hyperplasia can narrow the lumen

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Many studies have related extensive endothelial injury to neointimal hyperplasia develop‐ ment. Injury can be in the form of extreme venous distention, denudation of the endothelium itself, and degree of vasospasm overcome during harvest [28]. Intimal growth is stimulated by several factors including platelet derived growth factor, transforming growth factor beta, and epidermal growth factor which cause proliferation and subsequent invasion of the smooth muscle cells into the intimal layer [1]. When veins are injured, basic fibroblast growth factor is released from the endothelial cells and smooth muscle cells. This is a very potent mitogen that causes the increased production of multiple regulatory proteins, kinases, and genes that participate in DNA synthesis [29]. The sequential activation and inactivation of the cyclin dependent regulatory kinases (Cdk) leads the smooth muscle cells through the cell cycle [30]. Each cyclin exhibits a cell cycle phase specific pattern of expression with several cell cycle checkpoints at the G1/S station. At these points the kinases interact with a cyclin, specifically D and E interacting with Cdk 4/6, and 2. To progress the cell into the M phase cyclin B is activated. These Cdk proteins are inhibited by activating Cdk 1. The G1 Cdk is part of the retinoblastoma pocket proteins that when phosphorylated can sequester cell cycle regulatory transcription factors. This phosphorylation by retinoblastoma proteins as well as specific cylcin dependent kinases during late G1 leads to activation and release of genes that participate in DNA synthesis. It is this complex cascade of cellular activities that leads to proliferation of smooth muscle cells causing neointimal hyperplasia1, [30]. Further research has shown that other theories also exist as to the mechanism of neointimal hyperplasia that includes a role for perivascular fibroblasts and matrix metalloproteinases (MMP's). It is thought that fibroblasts invade through the media of the saphenous vein graft and differentiate into myofibroblasts. MMP's are the mediators of matrix deposition and degradation, which can cause neointimal hyperplasia. Theories exist that a strategy to avoid hyperplasia would be to use MMP inhibi‐ tors. MMPs compose a super family of 66 known zinc peptidases that degrade collagen, gelatin, and elastin31. MMPs are critical for cell growth and proliferation, cell migration, organ development, reproduction, and tissue remodeling. In all of these biological phenomena, matrix degradation is needed to facilitate changes in cell phenotype. For example, liganddependent cell-matrix associations are critical for modulating cell function, and matrix degradation. These interactions can thereby modulate responses of the cell to its microenvir‐
