While the ?response to injury? associated with pathologic vascular damage has been described as the initiator of vascular graft failure, there is very little information about the molecular mediator of this process. We propose that ATP released during surgical harvest of human saphenous vein activates purinergic receptors (P2X7R) leading to a cascade of events that promulgate and potentiate the response to injury. Understanding the role of ATP and P2X7R pathway activation in response to vascular injury will lead to specific modalities to prevent and treat the injury that occurs during surgical harvest of HSV. This work will also provide new insights in vascular biology with potential extensions to other applications such as vascular injury during angioplasty, transplantation, and trauma.

Public Health Relevance

Human saphenous vein (HSV) is the most commonly used conduits used to bypass occluded blood vessels in patients with cardiovascular diseases that are responsible for one of every five deaths. All previous therapeutic attempts at preventing the high rate of vein graft failure have failed in human trials suggesting that this represents an unmet clinical need. This proposal provides a unifying hypothesis for how surgical injury during harvest of HSV leads to a cascade of events that activate inflammation and intimal thickening leading to graft failure and provides new approaches to treat and prevent vein graft failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Reid, Diane M
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Vanderbilt University Medical Center
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Cheung-Flynn, Joyce; Song, Jun; Voskresensky, Igor et al. (2017) Limiting Injury During Saphenous Vein Graft Preparation For Coronary Arterial Bypass Prevents Metabolic Decompensation. Sci Rep 7:14179
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Luo, Weifeng; Feldman, Daniel; McCallister, Reid et al. (2017) P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis. Purinergic Signal 13:579-590
Guth, Christy M; Luo, Weifung; Jolayemi, Olukemi et al. (2017) Adenosine triphosphate as a molecular mediator of the vascular response to injury. J Surg Res 216:80-86
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Boire, Timothy C; Balikov, Daniel A; Lee, Yunki et al. (2016) Biomaterial-Based Approaches to Address Vein Graft and Hemodialysis Access Failures. Macromol Rapid Commun 37:1860-1880
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Hocking, Kyle M; Putumbaka, Gowthami; Wise, Eric S et al. (2016) Papaverine Prevents Vasospasm by Regulation of Myosin Light Chain Phosphorylation and Actin Polymerization in Human Saphenous Vein. PLoS One 11:e0154460
Wise, Eric S; Hocking, Kyle M; Luo, Weifeng et al. (2016) Traditional graft preparation decreases physiologic responses, diminishes viscoelasticity, and reduces cellular viability of the conduit: A porcine saphenous vein model. Vasc Med 21:413-421

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