Surgical vein bypass grafts fail principally due to development of neointimal hyperplasia, especially in the setting of low flow within the conduit. Inflammation stands as a pathologic feature of this process. While cytokines have been implicated in vein graft failure, the initiating factors and signaling mechanisms for their expression (as well as the biologic implications of these inflammatory mediators in vein wall adaptations) remain largely unknown. Prior studies by our group directly implicate the production of both the pro- inflammatory cytokine TNF-o_ and anti-inflammatory cytokine IL-10 in modulation of arterial wall adaptations to changes in wall shear. In recent work we demonstrated specific time and flow dependent cytokine signatures in the early arterialized vein graft. TNF-c_ expression is induced almost 200-fold within 24 hours in low flow grafts that subsequently develop robust intimal hyperplasia, while high flow promotes a delayed induction of IL-10 mRNA expression, which appears to protect against occlusive adaptations. This proposal moves forward by testing two linked mechanistic hypotheses: 1) Vein grafts develop neointimal hyperplasia by way of low wall shear induced pro-inflammatory cytokine driven mechanisms (soluble TNF-a signaling via the p55 receptor, leading to enhanced leukocyte mediated inflammation, and increased cell proliferation). Signaling pathways will be dissected by studying vein grafts in mice lacking soluble TNF-_, or the p55 or p75 receptor. Under differential flow environments, TNF- (_ signaling will be defined through inhibition by soluble receptors, adeno-associated virus (AAV)-delivered TNF receptor homologs, specific p55 or p75 TNF receptor antibodies, or TNF-o_ converting enzyme inhibition. 2) IL-10 production protects vein grafts from over exuberant occlusive wall adaptations via reduced inflammatory leukocyte infiltration, myofibroblast proliferation, and down-regulation of TNF- c?production. Vein grafts from IL-10 knockout mice will be examined, as well as conduits after treatment with exogenous IL-10 (both pharmacologic and AAV vIL-10). Based on new knowledge and skills obtained during the applicant's research training, the fundamental design of this initial independent proposal is to transfer basic cytokine biology to vascular biology, and throu.qh new mechanistic insights, translate these findin.qs into strate.qies to improve vein (]raft durability.
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