title: Endothelin-1 decreases endothelial PPARγ signaling and impairs angiogenesis after chronic intrauterine pulmonary hypertension.
abstract: Increased endothelin-1 (ET-1) disrupts angiogenesis in persistent pulmonary hypertension of the newborn (PPHN), but pathogenic mechanisms are unclear. Peroxisome proliferator activated receptor γ (PPARγ) is decreased in adult pulmonary hypertension, but whether ET-1-PPARγ interactions impair endothelial cell function and angiogenesis in PPHN remains unknown. We hypothesized that increased PPHN pulmonary artery endothelial cell (PAEC) ET-1 production decreases PPARγ signaling and impairs tube formation in vitro. Proximal PAECs were harvested from fetal sheep after partial ligation of the ductus arteriosus in utero (PPHN) and controls. PPARγ and phospho-PPARγ protein were compared between normal and PPHN PAECs ± ET-1 and bosentan (ETA/ETB receptor blocker). Tube formation was assessed in response to PPARγ agonists ± ET-1, N-nitro-l-arginine (LNA) (NOS inhibitor), and PPARγ siRNA. Endothelial NO synthase (eNOS), phospho-eNOS, and NO production were measured after exposure to PPARγ agonists and PPARγ siRNA. At baseline, PPHN PAECs demonstrate decreased tube formation and PPARγ protein expression and activity. PPARγ agonists restored PPHN tube formation to normal. ET-1 decreased normal and PPHN PAEC tube formation, which was rescued by PPARγ agonists. ET-1 decreased PPARγ protein and activity, which was prevented by bosentan. PPARγ agonists increased eNOS protein and activity and NO production in normal and PPHN PAECs. LNA inhibited the effect of PPARγ agonists on tube formation. PPARγ siRNA decreased eNOS protein and tube formation in normal PAECs. We conclude that ET-1 decreases PPARγ signaling and contributes to PAEC dysfunction and impaired angiogenesis in PPHN. We speculate that therapies aimed at decreasing ET-1 production will restore PPARγ signaling, preserve endothelial function, and improve angiogenesis in PPHN.
authors: Perinatal Research Facility, 13243 E. 23rd Ave., Mail Stop F441, Aurora, CO 80045. jason.gien@ucdenver.edu.
authors: David
authors: D
authors: Wolf
authors: Nancy
authors: N
authors: Tseng
authors: Gregory
authors: G
authors: Seedorf
authors: Gates
authors: G
authors: Roe
authors: Steven H
authors: SH
authors: Abman
authors: Jason
authors: J
authors: Gien
mesh_terms: D000818:Animals; D000077300:Bosentan; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D010547:Persistent Fetal Circulation Syndrome / Q000378:metabolism / Q000503:physiopathology; D011651:Pulmonary Artery / Q000473:pathology; D017466:Receptors, Endothelin / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D047495:PPAR gamma; D017466:Receptors, Endothelin; D013449:Sulfonamides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000077300:Bosentan
keywords: angiogenesis; endothelin-1 (ET-1); peroxisome proliferator activated receptor gamma (PPARγ); persistent pulmonary hypertension of the newborn (PPHN); pulmonary artery endothelial cell