Researchers test cellular ‘shipping containers’ for use in PH treatment
Novel strategy reduced pulmonary hypertension severity in rat model
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Treatment with molecular shipping containers called extracellular vesicles, loaded with a signaling molecule called cAMP, reduced the severity of pulmonary hypertension (PH) in a rat model of the disease, a new study reports.
The data indicated that these packages of signaling molecules, which they dubbed cAMP-EVs, reduced the abnormal growth of cells lining the blood vessels of the lungs under low-oxygen conditions.
“These results suggest that cAMP-EVs help [ease] pulmonary hypertension and further our understanding of cAMP signaling in the pulmonary circulation,” the researchers wrote, noting that the treatment “improved outcomes of pulmonary hypertension in rats.”
The study, “cAMP-enriched extracellular vesicles improve outcomes in pulmonary hypertension,” was published in the American Journal of Physiology-Lung Cellular and Molecular Physiology by researchers in the U.S.
Extracellular vesicles, or EVs, are essentially bubbles of cellular membrane. Within the body, EVs act as molecular shipping containers: Cells can load signaling molecules and other cargo into EVs, then send the EVs out into the body, where they will be taken up by other cells. This sending and receiving of EVs helps to coordinate many complex cellular processes throughout the body.
cAMP is short for cyclic adenosine monophosphate. It’s a signaling molecule that’s particularly important for regulating the activity of pulmonary artery endothelial cells, the cells that line the inside of blood vessels, known as the pulmonary arteries, that carry blood from the heart through the lungs. Abnormal growth of these cells is a hallmark of pulmonary hypertension. It causes these blood vessels to grow abnormally narrow, increasing the pressure inside them.
Available PH treatments don’t fix underlying dysfunction
The problem in PH, according to the scientists, is that available treatments don’t address the underlying problems.
“Current therapeutic strategies … alleviate the manifestations of pulmonary hypertension by modulating cAMP or cGMP [a related signaling molecule] signaling pathways within smooth muscle cells,” the scientists wrote. “However, these interventions fail to rectify the fundamental endothelial dysfunction and further do not intercede in the proliferative [growth] response leading to the vascular lesion formation characteristic of this pathology [disease].”
Given that cAMP is known to be important for regulating these disease-critical cells, a research team from the University of South Alabama wondered if it might be possible to treat pulmonary hypertension using EVs loaded up with extra cAMP.
To test this idea, the scientists conducted experiments in a rat model in which pulmonary hypertension was induced by exposing the animals to chronic hypoxia, or long-lasting low oxygen levels. Some of the rats were untreated, others were treated with control EVs, and a third group was treated with EVs loaded with cAMP — those referred to as cAMP-EVs.
Our data demonstrate that [this treatment strategy] can improve both [blood flow] and structural outcomes in pulmonary hypertension.
The results showed that rats treated with the cAMP-EVs had significantly reduced pressure in their pulmonary arteries, as well as less thickening of the arterial wall. The cAMP-EV-treated rats also had less enlargement of the right side of the heart, suggesting less stress on the part of the heart responsible for pumping blood to the lungs.
“Our data demonstrate that cAMP-EVs can improve both [blood flow] and structural outcomes in pulmonary hypertension,” the researchers wrote.
In further experiments using cell models, the researchers found that cAMP-EV treatment significantly reduced the growth of pulmonary artery endothelial cells, but only under low-oxygen conditions. Under normal oxygen conditions, cAMP-EV treatment had no effect on the growth of these blood vessel cells.
Collectively, the data support cAMP-EVs as a potential strategy to treat PH. However, the researchers noted that this study was limited to experiments in a rat model that may not fully capture the complexity of human disease. The team called for further work to test this strategy’s safety and effectiveness.
