Arch Bronconeumol. 2026 Sep 18:S0300-2896(26)00329-7. doi: 10.1016/j.arbres.2026.08.018. Online ahead of print.
ABSTRACT
OBJECTIVES: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, severe forms of pulmonary hypertension (PH) characterized by elevated mean pulmonary arterial pressure (mPAP) and ∼20% mortality at 3 years. PAH is defined by progressive obliterative vasculopathy, whereas CTEPH results from persistent pulmonary artery obstruction by fibrotic thrombotic material, leading to vascular remodelling, right ventricular hypertrophy, and heart failure.
METHODS: Endothelial colony-forming cells (ECFCs) derived from PAH and CTEPH patients and healthy-controls were analysed to identify disease-specific molecular and functional alterations. Transcriptomic profiling was integrated with functional assays, including global protein synthesis, mitochondrial bioenergetics, intracellular Ca2+ dynamics, and cellular ultrastructural assessment by transmission electron microscopy (TEM). The effects of riociguat, the approved therapy for inoperable or persistent post-surgical CTEPH, were also evaluated.
RESULTS: Significant differences in gene expression profiles were observed among PAH-ECFCs, CTEPH-ECFCs, and control-ECFCs. CTEPH-ECFCs, exhibited a unique upregulation of ribosomal and translation-related genes, accompanied by increased global protein synthesis. Network analysis revealed a highly connected ribosomal-translational hub within CTEPH transcriptome signature. CTEPH-ECFCs also exhibited mitochondrial remodelling, increased endoplasmic reticulum-mitochondria contacts, altered intracellular Ca2+ handling, and reduced maximal respiratory capacity. Riociguat did not reverse these abnormalities.
CONCLUSIONS: Dysregulated protein biosynthesis is a characteristic feature of CTEPH, distinguishing them from PAH. Our findings highlight a coordinated translation-mitochondria-MAM axis potentially involved in endothelial dysfunction and vascular remodelling, supporting the need for therapies targeting disease-specific molecular pathways beyond soluble guanylate cyclase stimulation.
PMID:42760207 | DOI:10.1016/j.arbres.2026.08.018