Scientists identify 2 key genes driving blood vessel damage in IPAH
Study: Team also developed diagnostic tool that could serve as risk biomarker
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Scientists in China have uncovered key genetic drivers of the abnormal thickening of lung blood vessels that is a hallmark of idiopathic pulmonary arterial hypertension (IPAH), where the cause is unknown.
By mapping individual lung cells and applying advanced tools, scientists identified two genes — POSTN and CCDC80 — that appeared to drive this abnormal thickening of blood vessels.
The team also developed a new diagnostic scoring tool that combines POSTN and CCDC80 activity levels to distinguish people with IPAH from those without it.
This tool “could serve as a potential early biomarker of IPAH risk, enabling earlier intervention and timely treatment,” and “may contribute to targeted therapies against vascular [blood vessel] remodeling treatment option for IPAH patients,” researchers wrote.
The findings were described in the study “Multi-omics integration study of vascular smooth muscle cell phenotypic conversion identified novel biomarkers in idiopathic pulmonary arterial hypertension,” which was published in Respiratory Research.
IPAH characterized by narrowing of blood vessels that supply lungs
IPAH is characterized by narrowing of the pulmonary arteries, blood vessels that supply the lungs, which restricts blood flow and elevates blood pressure. Such narrowing is driven by vascular remodeling, which involves the excessive growth of pulmonary artery smooth muscle cells (PASMCs), a type of muscle cell that makes up the pulmonary artery wall.
While most standard pulmonary arterial hypertension treatments ease symptoms by relaxing and widening arteries to improve blood flow and lower blood pressure, they don’t address the abnormal growth of PASMCs.
“A detailed molecular understanding of these alterations is essential for developing targeted therapies and improving clinical outcomes,” the researchers wrote.
To that end, the team of researchers in China used an advanced genetic tool called single-cell RNA sequencing to examine gene expression (activity) in more than 51,500 individual lung cells from six people with IPAH and nine healthy individuals.
The analysis identified 18 distinct cell clusters, grouped into nine major cell types. These included immune cells, as well as structural and support cells. One key finding was a shift in the balance of cell types in the lungs of IPAH patients. Several immune cells — especially T-cells, B-cells, and mast cells — were found in greater numbers in people with IPAH.
By analyzing each cell individually, the team found that most disease-related differences were linked to smooth muscle cells and fibroblasts, the most common cells in connective tissue.
Researchers identified three main groups, or clusters, of smooth muscle cells, two of which were confirmed to be vascular smooth muscle cells (VSMCs), which are part of the walls of blood vessels and include PASMCs. In IPAH samples, VSMCs showed greater integration with nearly all other lung cell types than in healthy controls.
Further analysis divided VSMCs into three distinct subtypes: contractile (blood vessel contraction), synthetic (production of structural components), and proliferative (cell growth). Researchers then used a method called pseudotime analysis, which arranged individual cells along a developmental pathway to understand how VSMCs change over time.
Results showed that the contractile type of VSMCs appeared at the beginning of this pathway, while the synthetic type appeared at the end. In other words, VSMCs transitioned from a contractile state, which helped blood vessels tighten and relax normally, toward a synthetic state, which produced structural materials that thickened and stiffened vessel walls.
Higher activity levels of 2 genes associated with increased risk of IPAH
From there, they identified 40 specific genes strongly linked to this transformation process, which they called phenotypic conversion regulatory genes. Two of these genes, POSTN and CCDC80, were identified as hub genes, or key drivers of the VSMC transformation process.
Using a well-established rat model of IPAH, the researchers found that the rat versions of the same two hub genes (POSTN and CCDC80) were significantly more active in the IPAH model than in healthy rats.
These results were confirmed in two independent human datasets, which also showed that POSTN and CCDC80 showed consistently higher activity in lung samples from IPAH patients.
Statistical models showed that higher activity levels of POSTN and CCDC80 were significantly associated with an increased risk of IPAH, whereas male sex was protective.
The team then developed a diagnostic tool, the VSMC Phenotypic Conversion Signature (VPCS), to help distinguish people with IPAH from those without the disease (controls). It combines activity levels of POSTN and CCDC80, as well as sex, into a single scoring system.
IPAH patients had significantly higher VPCS scores than controls. Moreover, the VPCS score performed better at identifying IPAH than any of its individual factors alone.
Finally, researchers exposed human PASMCs to low-oxygen (hypoxic) conditions and found that the activity of both CCDC80 and POSTN genes increased, like in IPAH patients. When these genes’ activity was suppressed, the excessive cell growth of PASMCs was partially reduced.
“Our integrative VSMC‑centered approach delineates dynamic state transitions in IPAH, nominates CCDC80 and POSTN as candidate regulators and biomarkers, and offers a practical framework for prioritizing targets from high‑dimensional datasets,” the team concluded.
