{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:48:47Z","timestamp":1793296127984,"version":"4.5.0"},"reference-count":63,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2014,2,15]]},"abstract":"<jats:p>Increased endothelin-1 (ET-1) disrupts angiogenesis in persistent pulmonary hypertension of the newborn (PPHN), but pathogenic mechanisms are unclear. Peroxisome proliferator activated receptor \u03b3 (PPAR\u03b3) is decreased in adult pulmonary hypertension, but whether ET-1-PPAR\u03b3 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 PPAR\u03b3 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. PPAR\u03b3 and phospho-PPAR\u03b3 protein were compared between normal and PPHN PAECs \u00b1 ET-1 and bosentan (ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub>receptor blocker). Tube formation was assessed in response to PPAR\u03b3 agonists \u00b1 ET-1, N-nitro-l-arginine (LNA) (NOS inhibitor), and PPAR\u03b3 siRNA. Endothelial NO synthase (eNOS), phospho-eNOS, and NO production were measured after exposure to PPAR\u03b3 agonists and PPAR\u03b3 siRNA. At baseline, PPHN PAECs demonstrate decreased tube formation and PPAR\u03b3 protein expression and activity. PPAR\u03b3 agonists restored PPHN tube formation to normal. ET-1 decreased normal and PPHN PAEC tube formation, which was rescued by PPAR\u03b3 agonists. ET-1 decreased PPAR\u03b3 protein and activity, which was prevented by bosentan. PPAR\u03b3 agonists increased eNOS protein and activity and NO production in normal and PPHN PAECs. LNA inhibited the effect of PPAR\u03b3 agonists on tube formation. PPAR\u03b3 siRNA decreased eNOS protein and tube formation in normal PAECs. We conclude that ET-1 decreases PPAR\u03b3 signaling and contributes to PAEC dysfunction and impaired angiogenesis in PPHN. We speculate that therapies aimed at decreasing ET-1 production will restore PPAR\u03b3 signaling, preserve endothelial function, and improve angiogenesis in PPHN.<\/jats:p>","DOI":"10.1152\/ajplung.00277.2013","type":"journal-article","created":{"date-parts":[[2013,12,14]],"date-time":"2013-12-14T05:18:03Z","timestamp":1386998283000},"page":"L361-L371","source":"Crossref","is-referenced-by-count":42,"title":["Endothelin-1 decreases endothelial PPAR\u03b3 signaling and impairs angiogenesis after chronic intrauterine pulmonary hypertension"],"prefix":"10.1152","volume":"306","author":[{"given":"David","family":"Wolf","sequence":"first","affiliation":[{"name":"Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado;"},{"name":"Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; 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