Endothelin-1 decreases endothelial PPAR{gamma} signaling and impairs angiogenesis after chronic intrauterine pulmonary hypertension

Increased endothelin-1 (ET-1) disrupts angiogenesis in persistent pulmonary hypertension of the newborn (PPHN), but pathogenic mechanisms are unclear. Peroxisome proliferator activated receptor (PPAR) is decreased in adult pulmonary hypertension, but whether ET-1-PPAR 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 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 and phospho-PPAR protein were compared between normal and PPHN PAECs ± ET-1 and bosentan (ETA/ETB receptor blocker). Tube formation was assessed in response to PPAR agonists ± ET-1, N-nitro-l-arginine (LNA) (NOS inhibitor), and PPAR siRNA. Endothelial NO synthase (eNOS), phospho-eNOS, and NO production were measured after exposure to PPAR agonists and PPAR siRNA. At baseline, PPHN PAECs demonstrate decreased tube formation and PPAR protein expression and activity. PPAR agonists restored PPHN tube formation to normal. ET-1 decreased normal and PPHN PAEC tube formation, which was rescued by PPAR agonists. ET-1 decreased PPAR protein and activity, which was prevented by bosentan. PPAR agonists increased eNOS protein and activity and NO production in normal and PPHN PAECs. LNA inhibited the effect of PPAR agonists on tube formation. PP...
Source: AJP: Lung Cellular and Molecular Physiology - Category: Respiratory Medicine Authors: Tags: ARTICLES Source Type: research