NDRG1 gene linked to blood vessel scarring in CTEPH: Study
Discovery could opens door for new targeted treatments
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A gene called NDRG1 may help drive blood vessel remodeling seen in chronic thromboembolic pulmonary hypertension (CTEPH) by shifting smooth muscle cells toward a scar-forming state, a study found.
“NDRG1 and related key gene axes may serve as potential therapeutic targets for CTEPH,” researchers wrote.
The study, “Single-cell transcriptomics reveals NDRG1/TGF β1 associated vascular smooth muscle cell phenotypic switching in chronic thromboembolic pulmonary hypertension,” was published in the Journal of Thrombosis and Thrombolysis.
Vascular smooth muscle cells may contribute to CTEPH
CTEPH is a form of pulmonary hypertension caused by the formation of blood clots in the pulmonary arteries, the blood vessels that carry blood from the heart to the lungs. Over time, these clots can become scar-like, blocking blood flow and raising pressure in the lungs’ blood vessels.
The standard treatment for eligible patients is pulmonary endarterectomy, a surgery to remove blood clots. However, some people continue to have high lung blood pressure after surgery, or develop it again, likely because of damage or structural alterations (remodeling) in small blood vessels in the lungs.
Researchers are still working to understand what drives this small-vessel remodeling in CTEPH. One possible contributor is a change in vascular smooth muscle cells, which normally help blood vessels contract and relax. In disease, these cells may shift into a fibrotic (scarring)-like state that can stiffen and narrow the vessels.
To better understand this process, researchers in China used two databases to analyze genetic data on pulmonary artery tissue from people with CTEPH and healthy donors, who were used as controls.
The goal was to identify the cellular and molecular changes that may drive smooth muscle cell remodeling in CTEPH, and to explore potential markers of disease activity or possible treatment targets.
CTEPH samples showed higher proportions of immune cells
Results showed 18 cell clusters with shared gene activity patterns. When compared with control tissues, CTEPH samples showed higher proportions of immune cells — including T-cells and monocytes/macrophages — as well as more smooth muscle cells.
Further analysis divided smooth muscle cells into four main states based on gene activity: contractile, synthetic, stress-responsive, and fibroblast-like.
The fibroblast-like smooth muscle cell group was markedly expanded in CTEPH, suggesting these cells may contribute to the scar-like remodeling that narrows and stiffens pulmonary blood vessels.
Gene activity patterns in CTEPH smooth muscle cells indicated the involvement of pathways involved in extracellular matrix organization — which provides biochemical and structural support to cells — and TGF-beta1, a molecule known to be involved in tissue scarring and remodeling.
Computational analysis suggested that smooth muscle cells may shift from a normal contractile state toward a fibroblast-like state in CTEPH, “further confirming the disease-driven shift in [smooth muscle cell] identity,” the team wrote.
NDRG1 protein levels higher in CTEPH relative to controls
To identify genes involved in this shift, the researchers combined computational analyses. From the two genes they identified, NDRG1 and TMSB4X, they selected NDRG1 for further study because it was consistently increased in CTEPH smooth muscle cells, while TMSB4X showed inconsistent results.
In pulmonary artery samples, NDRG1 protein levels were higher in CTEPH relative to controls. Other proteins of the TGF-beta1SMAD signaling pathway, as well as markers of fibrosis, were also increased. In contrast, SM22alpha, a marker of contractile smooth muscle cells, was reduced.
NDRG1 was mainly located in the smooth muscle cell layer of the pulmonary artery wall. In a larger group of CTEPH tissue samples, higher NDRG1 protein levels were significantly associated with higher pulmonary vascular resistance, a measure of how difficult it is for blood to flow through the lung vessels.
In additional experiments, low-oxygen (hypoxia) conditions increased NDRG1 levels in human pulmonary artery smooth muscle cells. When the researchers reduced NDRG1 levels using a genetic approach, they found that the activation of the TGF-beta1/SMAD biological pathway was lowered, and that the changes in markers of fibrosis and contractile cells were reversed.
“Collectively, these findings provide robust evidence that NDRG1 facilitates the hypoxia-induced phenotypic transition of [smooth muscle cells] toward a fibroblast-like state via the activation of the [TGF-beta1]/SMAD2 signaling axis,” the team concluded.
