Stimulation of angiogenesis involves the transition of endothelial cells from a quiescent to mitogenic and pro-migratory phenotype. Coordinate regulation of endothelial cell motility is an integral process in this phenomenon. However, specific molecular mechanisms responsible for directional migration of endothelial cells remain poorly characterized. VEGF(164) is a potent mediator of endothelial cell migration through activation of various cellular pathways including PI3K, Akt, and eNOS. Recent studies demonstrate that VEGF(164) stimulation increases adhesion molecule expression, such as intercellular adhesion molecule-1 (ICAM-1) expression, which may participate in VEGF mediated endothelial cell migration. However, there is a paucity of information detailing mechanisms of adhesion molecule regulation of angiogenesis. Therefore, this proposal will investigate the hypothesis that ICAM-1 governs VEGF(164) angiogenic activity by negatively regulating glutamate cysteine ligase (GCL-C) and subsequent glutathione (GSH) redox regulation of PTEN phosphatase, and modulates endothelial NOS activity and intracellular localization. This hypothesis will be examined by the following specific aims: 1) determine how ICAM-1 modulates GCL-C function and examine how GSH affects VEGF(164) ROS production, 2) determine how ICAM-1 governs eNOS cellular localization and activity in response to VEGF(164) stimulation, and 3) determine how increased intracellular levels of GSH affect PTEN regulation of VEGF(164) signaling. Data accumulated from these aims will provide unique insight into the role of ICAM-1 in controlling endothelial glutathione metabolism, eNOS activity and bioavailability, and PTEN activity during VEGF(164) mediated angiogenesis and endothelial cell chemotaxis. Completion of this project will significantly advance our understanding of specific mechanisms by which inflammatory adhesion molecules regulate angiogenesis and identify new targets for therapeutic angiogenic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080482-04
Application #
7662263
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$348,055
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Pathology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Bir, Shyamal C; Shen, Xinggui; Kavanagh, Terrance J et al. (2013) Control of angiogenesis dictated by picomolar superoxide levels. Free Radic Biol Med 63:135-42
Kolluru, Gopi Krishna; Bir, Shyamal C; Kevil, Christopher G (2012) Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int J Vasc Med 2012:918267
Bir, Shyamal C; Kolluru, Gopi K; Fang, Kai et al. (2012) Redox balance dynamically regulates vascular growth and remodeling. Semin Cell Dev Biol 23:745-57
Amin, Ali; Choi, Soo-Kyoung; Osman-Elazeik, Yehia et al. (2012) Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension. Pflugers Arch 464:583-92
Kevil, Christopher G; Lefer, David J (2012) Nitrite and nitrate: from bench to bedside. Nitric Oxide 26:195-6
Ostanin, Dmitry V; Kevil, Christopher G (2012) Radical innate regulation of autoimmune diabetes. Free Radic Biol Med 52:1698-9
Bir, Shyamal C; Kolluru, Gopi K; McCarthy, Paul et al. (2012) Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1? and vascular endothelial growth factor-dependent angiogenesis. J Am Heart Assoc 1:e004093
Allen, Jason D; Giordano, Tony; Kevil, Christopher G (2012) Nitrite and nitric oxide metabolism in peripheral artery disease. Nitric Oxide 26:217-22
Bir, Shyamal C; Pattillo, Christopher B; Pardue, Sibile et al. (2012) Nitrite anion stimulates ischemic arteriogenesis involving NO metabolism. Am J Physiol Heart Circ Physiol 303:H178-88
Pattillo, Christopher B; Bir, Shyamal; Rajaram, Venkat et al. (2011) Inorganic nitrite and chronic tissue ischaemia: a novel therapeutic modality for peripheral vascular diseases. Cardiovasc Res 89:533-41

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