Activation of PPARbeta/delta induces endothelial cell proliferation and angiogenesis.
OBJECTIVE
The role of the nuclear receptor peroxisome-proliferator activated receptor (PPAR)-beta/delta in endothelial cells remains unclear. Interestingly, the selective PPARbeta/delta ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPARbeta/delta in endothelial cell proliferation and angiogenesis.


RESULTS
Western blot analysis indicated PPARbeta/delta 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 PPARbeta/delta target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPARbeta/delta. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation.


CONCLUSIONS
PPARbeta/delta 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.
Piqueras
Laura
L
Cardiac, Vascular & Inflammation Research, William Harvey Research Institute, Barts and the London, Queen Mary University London, Charterhouse Sq, London EC1M 6BQ, UK.
Reynolds
Andrew R
AR
Hodivala-Dilke
Kairbaan M
KM
Alfranca
Arántzazu
A
Redondo
Juan M
JM
Hatae
Toshihisa
T
Tanabe
Tadashi
T
Warner
Timothy D
TD
Bishop-Bailey
David
D
D001013:Aorta, Thoracic / Q000166:cytology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A