title: The PPARδ ligand L-165041 inhibits VEGF-induced angiogenesis, but the antiangiogenic effect is not related to PPARδ.
abstract: Peroxisome proliferator-activated receptor (PPAR)δ is known to be expressed ubiquitously and involved in lipid and glucose metabolism. Recent studies have demonstrated that PPARδ is expressed in endothelial cells (ECs) and plays a potential role in endothelial survival and proliferation. Although PPARα and PPARγ are well recognized to play anti-inflammatory, antiproliferative, and antiangiogenic roles in ECs, the general effect of PPARδ on angiogenesis in ECs remains unclear. Thus, we investigated the effect of the PPARδ ligand L-165041 on vascular EC proliferation and angiogenesis in vitro as well as in vivo. Our data show that L-165041 inhibited VEGF-induced cell proliferation and migration in human umbilical vein ECs (HUVECs). L-165041 also inhibited angiogenesis in the Matrigel plug assay and aortic ring assay. Flow cytometric analysis indicated that L-165041 reduced the number of ECs in the S phase and the expression levels of cell cycle regulatory proteins such as cyclin A, cyclin E, CDK2, and CDK4; phosphorylation of the retinoblastoma protein was suppressed by pretreatment with L-165041. We confirmed whether these antiangiogenic effects of L-165041 were PPARδ-dependent using GW501516 and PPARδ siRNA. GW501516 treatment did not inhibit VEGF-induced angiogenesis, and transfection of PPARδ siRNA did not reverse this antiangiogenic effect of L-165041, suggesting that the antiangiogenic effect of L-165041 on ECs is PPARδ-independent. Together, these data indicate that the PPARδ ligand L-165041 inhibits VEGF-stimulated angiogenesis by suppressing the cell cycle progression independently of PPARδ. This study highlights the therapeutic potential of L-165041 in the treatment of many disorders related to pathological angiogenesis.
authors.affiliation: Division of Cardiovascular and Rare Diseases, Center for Biomedical Sciences, National Institute of Health, Korea.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Kuy-Sook
authors.initials: KS
authors.lastname: Lee
authors.forename: Hyun-Joung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Kwak
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Park
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D019925:Cyclin A / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D010642:Phenoxyacetates / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D020533:Angiogenesis Inhibitors; D019925:Cyclin A; D019927:Cyclin E; C425931:GW 501516; D047494:PPAR delta; D010642:Phenoxyacetates; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4