Sphingosine-1-phosphate (S1P) is a phosphorylated sphingolipid that mediates signaling via G-protein-coupled receptors. S1P signaling promotes an array of vascular cell behaviors important in angiogenesis and smooth muscle cell investment of nascent blood vessels. S1P signaling has not been considered to play an important role in the process of de novo formation of blood vessels, vasculogenesis. However, our recent findings indicate that vasculogenesis is dependent on S1P signaling. Specifically, S1P signaling is critical to promote migratory activities of angioblasts required for the expansion of vascular networks. A major tenet of this research project is that S1P-dependent angioblast motility has broad relevance to neovascular events in the embryo and adult. Not only can S1P-dependent angioblast motility be an important mechanism by which nascent embryonic vascular networks expand, but it may also be a critical aspect of the assembly of adult blood vessels from blood-derived endothelial cell progenitors/angioblasts. It is therefore necessary to understand the mechanisms by which S1P signaling influences angioblast motility and to establish its in vivo relevance in the context of physiological and pathological neovascular processes that involve adult vasculogenesis including tumor formation, wound healing and myocardial infarction. To address these objectives there are 3 specific aims: 1. Identify the specific S1P receptor(s) that are critical for mediating S1P signaling during vasculogenesis, 2. Characterize the involvement of integrins in S1P-induced angioblast motility, and 3. Determine the significance S1P signaling to adult vasculogenesis mediated by circulating angioblasts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080404-04
Application #
7424979
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
2005-07-15
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$276,869
Indirect Cost
Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Wilkerson, Brent A; Argraves, Kelley M (2014) The role of sphingosine-1-phosphate in endothelial barrier function. Biochim Biophys Acta 1841:1403-1412
Zyblewski, Sinai C; Argraves, W Scott; Graham, Eric M et al. (2012) Reduction in postoperative high-density lipoprotein cholesterol levels in children undergoing the Fontan operation. Pediatr Cardiol 33:1154-9
Wilkerson, Brent A; Grass, G Daniel; Wing, Shane B et al. (2012) Sphingosine 1-phosphate (S1P) carrier-dependent regulation of endothelial barrier: high density lipoprotein (HDL)-S1P prolongs endothelial barrier enhancement as compared with albumin-S1P via effects on levels, trafficking, and signaling of S1P1. J Biol Chem 287:44645-53
Argraves, Kelley M; Sethi, Amar A; Gazzolo, Patrick J et al. (2011) S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease. Lipids Health Dis 10:70
Bohonowych, Jessica E S; Peng, Shuping; Gopal, Udhayakumar et al. (2011) Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation. BMC Cancer 11:520
Argraves, Kelley M; Wilkerson, Brent A; Argraves, W Scott (2010) Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis. World J Biol Chem 1:291-7
Argraves, W Scott; Tanaka, Asashi; Smith, Elizabeth P et al. (2009) Fibulin-1 and fibrinogen in human atherosclerotic lesions. Histochem Cell Biol 132:559-65
Argraves, Kelley M; Gazzolo, Patrick J; Groh, Eric M et al. (2008) High density lipoprotein-associated sphingosine 1-phosphate promotes endothelial barrier function. J Biol Chem 283:25074-81
Gentile, Carmine; Fleming, Paul A; Mironov, Vladimir et al. (2008) VEGF-mediated fusion in the generation of uniluminal vascular spheroids. Dev Dyn 237:2918-25
Argraves, Kelley M; Argraves, W Scott (2007) HDL serves as a S1P signaling platform mediating a multitude of cardiovascular effects. J Lipid Res 48:2325-33