Low activity levels in a small RNA molecule called miR126 may be implicated in vascular remodeling — a hallmark feature of pulmonary hypertension (PH) — in the lungs of chronic obstructive pulmonary disease (COPD) patients regardless of whether or not they also have PH, a study reported.
This finding indicates that PH is not a determining factor in the blood vessel remodeling seen in people with COPD, according to the researchers.
The study, “Characterization of pulmonary vascular remodeling and MicroRNA-126-targets in COPD-pulmonary hypertension,” was published in the journal Respiratory Research.
miR126 works to regulate the migration of endothelial cells in lungs vessels
COPD is characterized by chronic inflammation that blocks the airways, causing cough with mucus, wheezing, and difficulty breathing.
PH, or increased blood pressure in the blood vessels that supply the lungs, can result from having COPD. Although the two diseases have similar features regarding alterations in pulmonary lung vessels and smooth muscle cells, COPD-PH lungs do not show the abnormal growth of endothelial cells — which line blood vessels — that form specific blood vessel lesions in pulmonary arterial hypertension.
The remodeling features of lung vessels in COPD-PH patients may be caused by the response of endothelial cells to chronic cigarette smoking. However, the underlying mechanisms are still unclear.
MicroRNAs, small RNA molecules that help to regulate the activity of genes, have been shown to play a key regulatory role in endothelial cells. In particular, miR126 is crucial for endothelial cell migration.
This miRNA has opposite functions depending on the size of the blood vessels. In large vessels, miR126 supports endothelial cells survival — in part by inhibiting the activity of a protein called SPRED1 — and in small vessels, it prevents the proliferation of these cells by blocking a protein called LAT1.
Previous studies have shown that cigarette smoke decreases the expression (activity) of miR126 in endothelial cells of the small vessels of the lungs. Additional research reported that miR126 targets a protein called ADAM9 that is involved in lung inflammation and damage in COPD.
Researchers in the U.S. conducted a study to characterize blood vessel remodeling in the lungs of people with COPD or COPD-PH and a history of tobacco smoking, and its association with miR126 and ADAM9 levels.
Lung tissue from COPD patients with and without PH was collected and compared with that of non-smokers and smokers without either of these diseases, both serving as controls.
Remodeling was analyzed according to pulmonary artery size and was measured by the levels of alpha-smooth muscle actin (alpha-SMA), a marker of smooth muscle cells and of myofibroblasts, cells important in tissue scarring.
The study also quantified the activity levels of miR126 and its targets, namely the genes that provide instructions for making the SPRED1, LAT1, and ADAM9 proteins.
Significantly higher levels of alpha-SMA were seen in the pulmonary arteries of people with COPD and COPD-PH compared with controls. Alpha-SMA levels particularly were increased in small pulmonary arteries and the lung’s smallest vessels.
Remodeling not linked to rise in mean pulmonary artery pressure
Researchers also found that greater remodeling in these blood vessels was not related to an increase in mean pulmonary artery pressure, a PH hallmark.
These findings “indicate that significant remodeling of the pulmonary vascular bed of small and microvascular size occurs before or independent of the clinical development of PH,” the scientists wrote.
Results also “highlight the importance of defining the mechanisms of pulmonary vascular injury and dysfunction which are associated with chronic smoking and COPD, rather than focusing solely on established COPD-PH,” they added.
In pulmonary vessels, people with COPD or COPD-PH also had significantly lower levels of endothelial cell markers and greater levels of ceramide, a mediator of programmed cell death. “These findings suggest endothelial cell and pulmonary arterial injury in COPD and COPD-PH,” the investigators wrote.
A significant reduction of miR126 expression also was found in lungs of COPD patients.
“Although miR126, by playing a key role in pulmonary vascular endothelial cell survival and repair is an attractive target for COPD-PH, other miRNAs may also be involved in the development of COPD and COPD-PH,” the scientists noted.
miR126 levels also decreased as ADAM9 gene expression increased, “suggesting it [ADAM9] is a direct target,” the team added.
ADAM9 levels were significantly higher in lungs of people with severe COPD, who are likely to have PH, as well as in individuals with confirmed COPD-PH when compared with controls. This was seen in small pulmonary arteries and in the smallest blood vessels.
“Decreased miR126 expression with reciprocal increase in ADAM9 may regulate endothelial cell survival and vascular remodeling in small pulmonary arteries and lung microvasculature in COPD and COPD-PH,” the investigators wrote.
Future studies are needed “to elucidate the role of cell-specific and intercellular communication between miR126 and ADAM9 in pulmonary vascular remodeling,” they added.