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Submitted on May 16, 2006
Accepted on October 10, 2006
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Induces Endothelial Cell Proliferation and Angiogenesis
From Cardiac, Vascular & Inflammation Research (L.P., T.D.W., D.B.-B.), William Harvey Research Institute; T Cell Adhesion and Disease Group (A.R.R., K.M.H.-D.), Centre for Tumour Biology, Institute of Cancer, and the CR-UK Clinical Centre, Barts, and The London, Queen Mary University London, Charterhouse Sq, London, UK; Centro de Biologia Molecular Severo Ochoa (A.A., J.M.R.), Consejo Superior de Investigaciones Cientificas (CSIC)-Universidad Autonoma de Madrid, Facultad de Ciencias, Cantoblanco, Spain; Department of Pharmacology (T.H., T.T.), National Cardiovascular Center Research Institute, Fujishiro-dai, Suita, Osaka, Japan.
* To whom correspondence should be addressed. E-mail: d.bishop-bailey{at}qmul.ac.uk.
Objective--The role of the nuclear receptor peroxisome-proliferator activated receptor (PPAR)-
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in endothelial cells remains unclear. Interestingly, the selective PPAR
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ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPAR
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in endothelial cell proliferation and angiogenesis.
Methods and Results--Western blot analysis indicated PPAR
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was expressed in primary human umbilical and aortic endothelial cells, and in the endothelial cell line, EAHy926. Treatment with GW501516 increased human endothelial cell proliferation and morphogenesis in 3-day cultures in vitro, endothelial cell outgrowth from murine aortic vessels in vitro, and angiogenesis in a murine matrigel plug assay in vivo. GW501516 induced vascular endothelial cell growth factor mRNA and peptide release, as well as adipose differentiation-related protein (ADRP), a PPAR
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target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPAR
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. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation.
Conclusions-- PPAR
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is a novel regulator of endothelial cell proliferation and angiogenesis through VEGF. The use of GW501516 to treat dyslipidemia may need to be carefully monitored in patients susceptible to angiogenic disorders.
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vascular endothelial growth factor
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