Despite advances in the surgical and catheter-based treatments for critical limb ischemia (CLI), 150,000 patients require lower limb amputation in the United States annually. Believing that an effective molecular therapy would have a significant clinical impact on the disability and limb loss rates in these patients, this study looks specifically at the role of endothelial nitric oxide synthase (eNOS) in collateral artery development (arteriogenesis). Because such development can reverse CLI, our central hypothesis maintains that the overexpression of eNOS will induce the ordered and sustainable development of collateral arteries in a way that will reverse CLI. Specifically, this research proposal aims 1) to identify the optimal gene transfer condition in a rat hind limb mode of ischemia; 2) to examine whether these eNOS gene transfer techniques can also reverse CLI clinically relevant animal models of diabetes, advanced age and hypercholesterolemia, and cigarette smoking; and 3) to characterize the molecular mechanisms by which eNOS overexpression increases arteriogenesis. To accomplish these aims, our research plan employs novel gene delivery techniques and sites of delivery. In particular, a unique method of intra-arterial gene transfer under vascular isolation that results in highly efficient and localized transgene expression will be used for gene transfer and laser Doppler perfusion imaging to measure dermal blood flow will facilitate the accomplishment of the above aims. Understanding the mechanisms by which eNOS exerts its powerful effects on arteriogenesis should provide additional insight into the fundamental mechanisms regulating arteriogenesis, and therefore open new therapeutic approaches for the treatment of CLI and other vascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Ershow, Abby
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Tie, Guodong; Messina, Katharine E; Yan, Jinglian et al. (2014) Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells. J Am Heart Assoc 3:e000241
Yan, Jinglian; Tie, Guodong; Xu, Ting Yu et al. (2013) Mesenchymal stem cells as a treatment for peripheral arterial disease: current status and potential impact of type II diabetes on their therapeutic efficacy. Stem Cell Rev 9:360-72
Yan, Jinglian; Tie, Guodong; Wang, Shouying et al. (2012) Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice. J Am Heart Assoc 1:e002238
Yan, Jinglian; Tie, Guodong; Messina, Louis M (2012) Tetrahydrobiopterin, L-arginine and vitamin C actsynergistically to decrease oxidative stress, increase nitricoxide and improve blood flow after induction of hindlimbischemia in the rat. Mol Med 18:676-84
Yan, Jinglian; Tie, Guodong; Hoffman, Ari et al. (2010) Oral tetrahydrobiopterin improves the beneficial effect of adenoviral-mediated eNOS gene transfer after induction of hindlimb ischemia. Mol Ther 18:1482-9
Park, Brian; Hoffman, Ari; Yang, Yagai et al. (2010) Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia in mice. J Vasc Surg 51:165-73
Li, J M; Newburger, P E; Gounis, M J et al. (2010) Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model. Gene Ther 17:1279-87
Tie, Guodong; Yan, Jinglian; Yang, Yagai et al. (2010) Oxidized low-density lipoprotein induces apoptosis in endothelial progenitor cells by inactivating the phosphoinositide 3-kinase/Akt pathway. J Vasc Res 47:519-30
Sneider, Erica B; Nowicki, Philip T; Messina, Louis M (2009) Regenerative medicine in the treatment of peripheral arterial disease. J Cell Biochem 108:753-61
Yan, Jinglian; Tie, Guodong; Park, Brian et al. (2009) Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells. J Vasc Surg 50:1412-22

Showing the most recent 10 out of 15 publications