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 remodelling 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 remodelling. 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 PH models prevented and reversed pulmonary and cardiac remodelling 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 signalling pathway to limit pulmonary vascular remodelling and PH.
['Jones|Carly|C|', 'Bisserier|Malik|M|', 'Bueno-Beti|Carlos|C|', 'Bonnet|Guillaume|G|', 'Neves-Zaph|Susana|S|', 'Lee|Sang-Yong|SY|', 'Milara|Javier|J|', 'Dorfmüller|Peter|P|', 'Humbert|Marc|M|', 'Leopold|Jane A|JA|', 'Hadri|Lahouaria|L|', 'Hajjar|Roger J|RJ|', 'Sassi|Yassine|Y|']
D015720:5'-Nucleotidase D000818:Animals D062186:Arterial Pressure D016022:Case-Control Studies D002465:Cell Movement D049109:Cell Proliferation D002478:Cells, Cultured D000242:Cyclic AMP D004195:Disease Models, Animal D006801:Humans D008168:Lung D008297:Male D008810:Mice, Inbred C57BL D010727:Phosphoric Diester Hydrolases D000081029:Pulmonary Arterial Hypertension D011651:Pulmonary Artery D011755:Pyrophosphatases D017207:Rats, Sprague-Dawley D015290:Second Messenger Systems D055571:Secretory Pathway D066253:Vascular Remodeling
Pulmonary hypertension Extracellular cAMP Cyclic nucleotides Vascular signalling