Transcriptomic and functional profiling of endothelial colony-forming cells (ECFCs) from PAH patients, CTEPH patients, and healthy controls to identify disease-specific molecular alterations, including the effect of riociguat on CTEPH-ECFC abnormalities.
CTEPH-ECFCs showed a unique upregulation of ribosomal and translation-related genes with increased global protein synthesis, mitochondrial remodelling, increased ER-mitochondria contacts (MAMs), altered intracellular Ca²⁺ handling, and reduced maximal respiratory capacity — a profile distinct from PAH-ECFCs; riociguat did not reverse these abnormalities.
ECFCs are circulating surrogate cells and may not fully reflect the transcriptomic state of pulmonary vascular endothelium in situ; sample sizes for rare disease groups are likely small; the study is observational/translational without in vivo validation of the identified pathways.
CTEPH has a distinct molecular signature — a translation-mitochondria-MAM axis — that riociguat does not correct, suggesting that approved soluble guanylate cyclase–targeted therapy may be insufficient and that disease-specific pathways (ribosomal/translational) warrant investigation as therapeutic targets in inoperable or persistent CTEPH.
