EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling.

Lu A, Zuo C, He Y, Chen G, Piao L, Zhang J, Xiao B, Shen Y, Tang J, Kong D, Alberti S, Chen D, Zuo S, Zhang Q, Yan S, Fei X, Yuan F, Zhou B, Duan S, Yu Y, Lazarus M, Su Y, Breyer RM, Funk CD, Yu Y
J Clin Invest. 2015 125 (3): 1228-42

PMID: 25664856 · PMCID: PMC4362262 · DOI:10.1172/JCI77656

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.

MeSH Terms (17)

Animals Cell Hypoxia Cells, Cultured Extracellular Matrix Extracellular Matrix Proteins Hypertension, Pulmonary Male Mice, Inbred C57BL Mice, Knockout Pulmonary Artery Rats, Sprague-Dawley Receptors, Prostaglandin E, EP3 Subtype rho GTP-Binding Proteins Signal Transduction Sulfonamides Transforming Growth Factor beta1 Vascular Remodeling

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