Published online before print October 26, 2006, doi: 10.1161/01.ATV.0000250972.83623.61
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© 2007 American Heart Association, Inc.
Vascular Biology |
Activation of PPARß/
Induces Endothelial Cell Proliferation and Angiogenesis
From Cardiac, Vascular & Inflammation Research (L.P., T.D.W., D.B.-B.), William Harvey Research Institute; 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. Current address for J.M.R.: Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernandez Almagro 3, Madrid 28029.
Correspondence to David Bishop-Bailey, From Cardiac, Vascular & Inflammation Research (L.P., T.D.W., D.B.-B.), William Harvey Research Institute, Barts and the London, Queen Mary University London, Charterhouse Sq, London EC1M 6BQ. E-mail d.bishop-bailey{at}qmul.ac.uk
Objective— The role of the nuclear receptor peroxisome-proliferator activated receptor (PPAR)-ß/
in endothelial cells remains unclear. Interestingly, the selective PPARß/ ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPARß/ in endothelial cell proliferation and angiogenesis.
Methods and Results— Western blot analysis indicated PPARß/ 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 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 PPARß/ target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPARß/. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation.
Conclusions— PPARß/ 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.
PPARß/ is expressed in vascular endothelial cells; however, its roles remain unclear. The PPARß/ ligand GW501516 induced endothelial proliferation and angiogenesis. The clinical use of GW501516 in dyslipidemia may therefore need to be monitored for angiogenic processes.
Key Words: angiogenesis • endothelial cells • PPARß/ • vascular endothelial growth factor
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