title: Rosiglitazone antagonizes vascular endothelial growth factor signaling and nuclear factor of activated T cells activation in cardiac valve endothelium.
abstract: Nuclear factor of activated T cells, Cytoplasmic 1 (NFATc1) is required for heart valve formation. Vascular endothelial growth factor (VEGF) signaling, mediated by NFATc1 activation, positively regulates growth of valvular endothelial cells. However, regulators of VEGF/NFATc1 signaling in valve endothelium are poorly understood. Peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits NFATc1 activity in T cells and cardiomyocytes, but it is not known if PPARgamma controls NFATc1 function in endothelial cells. The authors hypothesize PPARgamma antagonizes VEGF signaling in valve endothelium by inhibiting NFATc1. Endothelial cells isolated from human valve leaflet tissue were shown by immunocytochemistry to express the endothelial-specific markers von Willebrand factor (vWF) and platelet endothelial cell adhesion molecule (PECAM)-1. VEGF-induced proliferation and migration of human pulmonary valve endothelial cells (HPVECs) were inhibited by rosiglitazone (ROSI), a specific ligand of PPARgamma activation, suggesting that PPARgamma disrupts VEGF signaling in the valve endothelium. ROSI also antagonized VEGF-mediated NFATc1 nuclear translocation in HPVECs, suggesting that PPARgamma inhibits VEGF signaling of NFATc1 activation in the valve. The effect of ROSI on nonvalve human umbilical vein endothelial cells (HUVECs) was tested in parallel and a similar inhibition of NFATc1 activation was observed. These data provide the first demonstration that ROSI negatively regulates VEGF signaling in the valve endothelium by a mechanism involving NFATc1 activation and nuclear translocation.
authors.affiliation: Department of Surgery, Medical College of Wisconsin and Children's Research Institute, Milwaukee, Wisconsin 53226, USA. sandert@mcw.edu
authors.forename: Tara L
authors.initials: TL
authors.lastname: Sander
authors.forename: LeAnne
authors.initials: L
authors.lastname: Noll
authors.forename: Denise B
authors.initials: DB
authors.lastname: Klinkner
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.forename: Beixin J
authors.initials: BJ
authors.lastname: He
authors.forename: Sushma
authors.initials: S
authors.lastname: Kaul
authors.forename: Steven D
authors.initials: SD
authors.lastname: Zangwill
authors.forename: James S
authors.initials: JS
authors.lastname: Tweddell
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
authors.forename: Keith T
authors.initials: KT
authors.lastname: Oldham
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D002648:Child; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors; D006351:Heart Valves / Q000166:cytology*; D006801:Humans; D050778:NFATC Transcription Factors / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D000077154:Rosiglitazone; D005346:Fibroblast Growth Factors