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 proinflammatory cytokine TNF-alpha 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-alpha 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-alpha 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-alpha or the p55 or p75 receptor. Under differential flow environments, TNF-alpha 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-alpha 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-alpha 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 through new mechanistic insights, translate these findings into strateqies to improve vein (draft durability).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079135-03
Application #
7247144
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Srinivas, Pothur R
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$202,491
Indirect Cost
Name
University of Florida
Department
Surgery
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Yu, Peng; Nguyen, Binh T; Tao, Ming et al. (2014) Diet-induced obesity drives negative mouse vein graft wall remodeling. J Vasc Surg 59:1670-6
Mauro, Christine R; Ilonzo, Godfrey; Nguyen, Binh T et al. (2013) Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue. Am J Surg 206:241-4
Yu, Peng; Nguyen, Binh T; Tao, Ming et al. (2013) Lack of interleukin-1 signaling results in perturbed early vein graft wall adaptations. Surgery 153:63-9
Mauro, Christine R; Nguyen, Binh T; Yu, Peng et al. (2013) Inflammatory ""adiposopathy"" in major amputation patients. Ann Vasc Surg 27:346-52
Nguyen, Binh T; Yu, Peng; Tao, Ming et al. (2013) Perivascular innate immune events modulate early murine vein graft adaptations. J Vasc Surg 57:486-492.e2
Tao, Ming; Yu, Peng; Nguyen, Binh T et al. (2013) Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 33:311-20
Favreau, John T; Nguyen, Binh T; Gao, Ian et al. (2012) Murine ultrasound imaging for circumferential strain analyses in the angiotensin II abdominal aortic aneurysm model. J Vasc Surg 56:462-9
Fu, Chunhua; Yu, Peng; Tao, Ming et al. (2012) Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations. Arterioscler Thromb Vasc Biol 32:2418-26
Mitsouras, Dimitris; Vemula, Praveen Kumar; Yu, Peng et al. (2011) Immobilized contrast-enhanced MRI: Gadolinium-based long-term MR contrast enhancement of the vein graft vessel wall. Magn Reson Med 65:176-83
Yu, Peng; Nguyen, Binh T; Tao, Ming et al. (2011) Mouse vein graft hemodynamic manipulations to enhance experimental utility. Am J Pathol 178:2910-9

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