The mechanisms of successful long-term vein graft adaptation to the arterial environment without excessive intimal thickening are still not completely understood. Several members of the Ephrin-Eph pathway have recently been described as developmentally specified critical determinants of vessel identity, with Ephrin- B2 ligand an embryonic determinant of arteries and Eph-B4 receptor an embryonic determinant of veins. We have recently shown in both humans and rats that diminished Eph-B4 expression and loss of venous identity is associated with intimal thickening during vein graft adaptation, and that VEGF-A is an upstream inhibitor of intimal thickening. In addition, we showed increased amounts of the vasculoprotective protein Nogo-B during both human and rat vein graft adaptation. However, it is currently not established whether plasticity exists in vessel specification genes in adults, whether the Ephrin-Eph pathway plays a mechanistic role during vein graft adaptation to the arterial environment, or whether Nogo-B is linked to Eph-B4 signaling pathways. We present our exciting new data that: 1) diminished Eph-B4 gene expression and immunoreactive protein is associated with intimal thickening in the mouse model of vein graft adaptation;2) we can manipulate Eph-B4 signaling in vivo to directly test the role of Eph-B4 in vein graft adaptation in mice;3) Nogo-B inhibits intimal thickening during vein graft adaptation;and 4) Nogo-B protein is increased in vein grafts treated with siRNA directed against VEGF-A, linking the Nogo-B pathway with the VEGF-A-Eph-B4 pathway. We hypothesize that decreased expression of venous specification genes without concomitant expression of arterial specification genes leads to excessive intimal thickening, and ultimately vein graft failure. We will test our hypothesis with the following specific aims:
Aim I. To determine whether Eph-B4 signaling mediates intimal thickening during vein graft adaptation.
Aim II. To determine whether VEGF-A inhibition of intimal thickening is mediated by regulation of vessel identity and Eph-B4 expression.
Aim III. To determine whether the vasculoprotective effects of Nogo-B during vein graft adaptation are mediated by regulation of Eph-B4 function. The studies are innovative in that analyses of vein graft identity have not been previously performed in mice, and plasticity of the Eph-B4 pathway has not been previously demonstrated in adults. At the completion of these studies, we expect to identify a role for Eph-B4 in vein graft adaptation and to determine whether strategies to limit intimal thickening during vein graft adaptation by altering vessel identity will be a novel approach for a human clinical trial.

Public Health Relevance

Significant numbers of surgically placed coronary and peripheral vein grafts continue to fail due to excessive intimal thickening with resultant patient morbidity and mortality. Improving results of long-term myocardial revascularization and limb salvage remain critically dependent on understanding the mechanisms of excessive intimal thickening during vein graft adaptation to the arterial environment. This proposal takes a novel approach, manipulation of vessel identity, to control intimal thickening.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL095498-01
Application #
7628286
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Reid, Diane M
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2009-04-15
Budget End
2010-03-31
Support Year
1
Fiscal Year
2009
Total Cost
$413,750
Indirect Cost
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yu, Jun; Dardik, Alan (2018) A Murine Model of Hind Limb Ischemia to Study Angiogenesis and Arteriogenesis. Methods Mol Biol 1717:135-143
Protack, Clinton D; Foster, Trenton R; Hashimoto, Takuya et al. (2017) Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency. Sci Rep 7:15386
Bai, Hualong; Li, Xin; Hashimoto, Takuya et al. (2017) Patch Angioplasty in the Rat Aorta or Inferior Vena Cava. J Vis Exp :
Wang, Mo; Collins, Michael J; Foster, Trenton R et al. (2017) Eph-B4 mediates vein graft adaptation by regulation of endothelial nitric oxide synthase. J Vasc Surg 65:179-189
Kuwahara, Go; Hashimoto, Takuya; Tsuneki, Masayuki et al. (2017) CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation. Arterioscler Thromb Vasc Biol 37:1147-1156
Sadaghianloo, Nirvana; Yamamoto, Kota; Bai, Hualong et al. (2017) Increased Oxidative Stress and Hypoxia Inducible Factor-1 Expression during Arteriovenous Fistula Maturation. Ann Vasc Surg 41:225-234
Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth et al. (2017) Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia. Sci Rep 7:40142
Assi, Roland; Foster, Trenton R; He, Hao et al. (2016) Delivery of mesenchymal stem cells in biomimetic engineered scaffolds promotes healing of diabetic ulcers. Regen Med 11:245-60
Bai, Hualong; Wang, Mo; Foster, Trenton R et al. (2016) Pericardial patch venoplasty heals via attraction of venous progenitor cells. Physiol Rep 4:
Bai, Hualong; Kuwahara, Go; Wang, Mo et al. (2016) Pretreatment of pericardial patches with antibiotics does not alter patch healing in vivo. J Vasc Surg 63:1063-73

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