Vascular endothelial growth factor (VEGF) has long been considered a target for clinical intervention; however, its clinical relevance has yet to be proven. Elucidation of effectors downstream of VEGF may provide more sensitive drug targets for the use in angiogenic therapies for the treatment of cancer and cardiovascular diseases. Although precise mechanisms regulating angiogenesis remain to be delineated, it is generally accepted that VEGF is the main inducer of the angiogenic switch; its induction is controlled in part by hypoxia, it is expressed by a majority of tumor cells and it promotes endothelial cell (EC) proliferation, migration and tube formation. We have uncovered a novel VEGF signaling pathway that leads to the regulation of Akt3 through the sphingosine-1 -phosphate (S1P) receptor, Edg3, a G-protein coupled transmembrane receptor involved in the regulation of angiogenesis. Gene blocking has defined a discrete role for Akt3 downstream of VEGF signaling, the control of mitochondria! biogenesis. This pathway is independent of other Akt family members. Signaling pathways that coordinate mitochondrial biogenesis with cellular energy demands as they relate to processes such as angiogenesis, that involve new tissue production are poorly understood. The findings presented here support the hypothesis that Akt3 is a key regulator of VEGF-induced cellular energetics in primary endothelial cells. Experimentation is designed to 1. test and extend the model that VEGF acts through the Edg3 receptor to promote Akt3 expression, 2. determine the mechanism Akt3 regulates mitochondrial biogenesis and 3. use the Akt3 null animals to confirm the relevance of Akt3 in the regulation of mitochondrial biogenesis. Delineation of this novel pathway and its regulation of mitochondrial biogenesis is a prerequisite to designing new angiogenic therapies for the treatment of a broad range of human diseases linked to mitochondrial function. In addition these findings may provide important insights into fundamental processes beyond the scope of angiogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL084565-01A1
Application #
7192769
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
Project Start
2007-01-19
Project End
2011-12-31
Budget Start
2007-01-19
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$292,000
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
Corum, Daniel G; Tsichlis, Philip N; Muise-Helmericks, Robin C (2014) AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1. FASEB J 28:395-407
Gentile, Carmine; Muise-Helmericks, Robin C; Drake, Christopher J (2013) VEGF-mediated phosphorylation of eNOS regulates angioblast and embryonic endothelial cell proliferation. Dev Biol 373:163-75
Liby, Tiera A; Spyropoulos, Perry; Buff Lindner, Haley et al. (2012) Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells. Int J Cancer 130:532-43
Beeson, Craig C; Beeson, Gyda C; Buff, Haley et al. (2012) Integrin-dependent Akt1 activation regulates PGC-1 expression and fatty acid oxidation. J Vasc Res 49:89-100
Lindner, Haley Buff; Zhang, Aiguo; Eldridge, Juanita et al. (2011) Anti-bacterial effects of poly-N-acetyl-glucosamine nanofibers in cutaneous wound healing: requirement for Akt1. PLoS One 6:e18996
Scherer, Saja Sandra; Pietramaggiori, Giorgio; Matthews, Jasmine et al. (2009) Poly-N-acetyl glucosamine nanofibers: a new bioactive material to enhance diabetic wound healing by cell migration and angiogenesis. Ann Surg 250:322-30
Vournakis, John N; Eldridge, Juanita; Demcheva, Marina et al. (2008) Poly-N-acetyl glucosamine nanofibers regulate endothelial cell movement and angiogenesis: dependency on integrin activation of Ets1. J Vasc Res 45:222-32
Wright, Gary L; Maroulakou, Ioanna G; Eldridge, Juanita et al. (2008) VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase. FASEB J 22:3264-75