on October 26, 2006
Published online before print October 26, 2006, doi: 10.1161/01.ATV.0000250972.83623.61
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Submitted on May 16, 2006
Accepted on October 10, 2006
Activation of PPAR
/
Induces Endothelial Cell Proliferation and Angiogenesis
Laura Piqueras ;
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)-
/
in endothelial cells remains unclear. Interestingly, the selective PPAR/ ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPAR/ in endothelial cell proliferation and angiogenesis.
Methods and Results--Western blot analysis indicated PPAR/ 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/ target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPAR/. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation.
Conclusions-- PPAR/ 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.
Key words: angiogenesis • endothelial cells • PPAR
/ •
vascular endothelial growth factor
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