A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism.

AIMS: Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodeling in the pathogenesis of pulmonary hypertension (PH). METHODS AND RESULTS: The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodeling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo pulmonary hypertension models prevented and reversed pulmonary and cardiac remodeling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway. CONCLUSIONS: Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signaling pathway to limit pulmonary vascular remodeling and PH. TRANSLATIONAL PERSPECTIVE: Lungs samples from patients with clinical PAH and from animals with PH display increased cyclic AMP-metabolizing enzymes expression levels. Our results indicate that an endogenous extracellular cAMP pathway is activated during PH and attempts to counteract vascular remodeling. Additionally, our study demonstrates that extracellular-cAMP inhibits chronic hypoxia-induced PH in mice and MCT-induced PH in rats by activating the A2R/PKA/CREB/p53/Cyclin D1 pathway. Importantly, PAH patients display an inactive PKA/CREB/p53/Cyclin D1 pathway that could be stimulated by extracellular-cAMP. Targeting the extracellular cAMP pathway may represent a novel therapeutic approach for the treatment of pulmonary arterial hypertension