| First Author | Lu A | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 3 | Pages | 1228-42 |
| PubMed ID | 25664856 | Mgi Jnum | J:220545 |
| Mgi Id | MGI:5635323 | Doi | 10.1172/JCI77656 |
| Citation | Lu A, et al. (2015) EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-beta1 signaling. J Clin Invest 125(3):1228-42 |
| abstractText | 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 EP3alpha and EP3beta, but not EP3gamma, isoforms diminished hypoxia-induced TGF-beta1 activation. Expression of either EP3alpha or EP3beta in EP3-deficient PASMCs restored TGF-beta1 activation in response to hypoxia. EP3alpha/beta 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-beta1 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. |
