cAMP-enriched extracellular vesicles improve outcomes in pulmonary hypertension

Extracellular vesicles (EVs) containing cyclic adenosine monophosphate (cAMP-EVs) activate signaling based on protein kinase A in recipient endothelial cells, but limited information is available about the function of cAMP-EVs under physiologic or pathologic conditions. We evaluated the effects of treatment with cAMP-EVs in Sprague-Dawley rats with hypoxia-induced pulmonary hypertension. Rats were exposed to hypoxia (10% oxygen) or normoxia for 3 wk, and the hypoxic rats received no injection or tail vein injection with cAMP-EVs or control EVs during the final 3 days of hypoxia. The ratio of pulmonary artery acceleration time to pulmonary artery ejection time was higher, and the Fulton index was lower, in hypoxic rats treated with cAMP-EVs compared with those receiving no treatment. Confocal microscopy with PKH red-stained EVs showed higher fluorescence in lung tissue from hypoxic rats treated with cAMP-EVs versus no treatment. Hypoxic rats treated with cAMP-EVs had lower arterial wall thickness, higher protein kinase A activity, and higher endothelial nitric oxide synthase phosphorylation than untreated rats. Our coculture studies showed that stimulation of pulmonary endothelial cells with cAMP-EVs under hypoxic conditions inhibited PASMC proliferation, whereas no significant effect was observed under normoxia. These results provide evidence that second messenger molecules, such as cAMP packaged in EVs, help improve pathological conditions, including pulmonary hypertension.<b>NEW & NOTEWORTHY</b> Treatment with extracellular vesicles containing cyclic adenosine monophosphate (cAMP-EVs) improved outcomes of pulmonary hypertension in rats with hypoxia-induced pulmonary hypertension. Furthermore, the signaling events relative to these outcomes are likely endothelial-dependent and do not require the β-adrenergic receptor. These results suggest that cAMP-EVs help improve pulmonary hypertension and further our understanding of cAMP signaling in the pulmonary circulation.