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There is evidence of scant IP and PPAR\u03b3 expression but stable prostanoid EP<jats:sub>4<\/jats:sub> receptor (EP<jats:sub>4<\/jats:sub>) expression in IPAH patients. Both IP and EP<jats:sub>4<\/jats:sub> functionally couple with stimulatory G protein (G<jats:sub>s<\/jats:sub>), which activates signal transduction. We investigated the effect of an EP<jats:sub>4<\/jats:sub>-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP<jats:sub>4<\/jats:sub>, and PPAR\u03b3 expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP<jats:sub>4<\/jats:sub> agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPAR\u03b3 but stable expression of EP<jats:sub>4<\/jats:sub> was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPAR\u03b3 in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP<jats:sub>4<\/jats:sub> antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPAR\u03b3 in the activity of this EP<jats:sub>4<\/jats:sub> agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP<jats:sub>4<\/jats:sub> agonist L-902,688 reverses vascular remodeling by activating PPAR\u03b3. This study identified a novel EP<jats:sub>4<\/jats:sub>-PKA-PPAR\u03b3 pathway, and we propose EP<jats:sub>4<\/jats:sub> as a potential therapeutic target for PAH. <\/jats:p>","DOI":"10.1152\/ajplung.00245.2017","type":"journal-article","created":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T14:05:28Z","timestamp":1510841128000},"page":"L349-L359","source":"Crossref","is-referenced-by-count":28,"title":["Prostanoid EP<sub>4<\/sub> agonist L-902,688 activates PPAR\u03b3 and attenuates pulmonary arterial hypertension"],"prefix":"10.1152","volume":"314","author":[{"given":"Hsin-Hsien","family":"Li","sequence":"first","affiliation":[{"name":"Department of Respiratory Therapy, Chang-Gung University College of Medicine, Tao-Yuan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsao-Hsun","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital and National Taiwan 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