title: EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling.
abstract: Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3β, but not EP3γ, isoforms diminished hypoxia-induced TGF-β1 activation. Expression of either EP3α or EP3β in EP3-deficient PASMCs restored TGF-β1 activation in response to hypoxia. EP3α/β activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro-MMP-2 and promoting TGF-β1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension.
authors: Ankang
authors: A
authors: Lu
authors: Caojian
authors: C
authors: Zuo
authors: Yuhu
authors: Y
authors: He
authors: Guilin
authors: G
authors: Chen
authors: Lingjuan
authors: L
authors: Piao
authors: Jian
authors: J
authors: Zhang
authors: Bing
authors: B
authors: Xiao
authors: Yujun
authors: Y
authors: Shen
authors: Juan
authors: J
authors: Tang
authors: Deping
authors: D
authors: Kong
authors: Sara
authors: S
authors: Alberti
authors: Di
authors: D
authors: Chen
authors: Shenkai
authors: S
authors: Zuo
authors: Qianqian
authors: Q
authors: Zhang
authors: Shuai
authors: S
authors: Yan
authors: Xiaochun
authors: X
authors: Fei
authors: Fei
authors: F
authors: Yuan
authors: Bin
authors: B
authors: Zhou
authors: Shengzhong
authors: S
authors: Duan
authors: Yu
authors: Y
authors: Yu
authors: Michael
authors: M
authors: Lazarus
authors: Yunchao
authors: Y
authors: Su
authors: Richard M
authors: RM
authors: Breyer
authors: Colin D
authors: CD
authors: Funk
authors: Ying
authors: Y
authors: Yu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011651:Pulmonary Artery / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D066253:Vascular Remodeling; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein; D000096926:Benzenesulfonamides
chemical_list: D016326:Extracellular Matrix Proteins; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C000595268:5-bromo-2-methoxy-N-(3-(naphthalen-2-yl-methylphenyl)acryloyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C545648:Ptger3 protein, mouse; C526380:RhoA protein, mouse