Abstract 447: The Role of Extracellular cAMP in the Pathogenesis of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is an uncommon, progressive, life-threatening and often fatal disease. Despite advances in PAH therapy, there is no cure for PAH, and new therapies need to be developed. Activation of G-protein-coupled receptors stimulates adenylyl cyclase, leading in vascular smooth muscle cells to an increase in intracellular cyclic adenosine monophosphate (cAMP) formation and reduced cell proliferation in vitro and in vivo . Yet, the last two decades of research have shown that there is more to the role of cAMP than ever expected from this molecule. Stimulated cells transport cAMP outside the cells, a process that is mediated by the multidrug resistance-associated proteins (MRPs). Herein, we investigated the role of extracellular cAMP in the lung and asked whether it may act on pulmonary vascular remodeling. By employing a fluorescence resonance energy transfer (FRET)-based sensor, we found that extracellular cAMP activates intracellular cAMP formation in human pulmonary artery smooth muscle cells (hPASMC) and endothelial cells (hPAEC). Extracellular cAMP, via binding of its metabolite adenosine to the type A2 receptor, reduced hPASMC and hPAEC proliferation and migration by controlling the PKA/CREB pathway. To test for a role of extracellular cAMP in the pulmonary vasculature, we used rat-monocrotaline and mouse-hypoxia as in vivo models of PAH. Rats treated with monocrotaline developed PAH with increased pulmonary artery pressures (PAP) and right ventricular (RV) hypertrophy. Extracellular cAMP infusion significantly prevented and reversed these structural changes. Extracellular-cAMP-treated rats displayed lower RV systolic pressure and Fulton index, as well as decreased PAP. In line with these observations, we found infused cAMP to potently repress RV hypertrophy, RV systolic pressure, perivascular lung fibrosis and pulmonary arteries remodeling in mice exposed to Sugen5416 and chronic hypoxia. Together, our results assign extracellular cAMP a potent regulatory role in pulmonary vascular cells, and suggest targeting the extracellular cAMP signaling pathway to limit pulmonary vascular remodeling and PAH.