Endothelial dysfunction in patients with chronic thromboembolic pulmonary hypertension (CTEPH)

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Rationale: Hyperproliferative phenotype of CTEPH patient9s cells obtained from pulmonary endarterectomy (PEA) specimens may suggest mitochondrial involvement in CTEPH etiopathogenesis. We aimed to develop an in vitro model of CTEPH using patient-derived cell lines and to assess potential mitochondrial disturbances. Methods: Endothelial cells isolated from specimens obtained at PEA, had a cobblestone morphology, endothelial phenotype and functionality (tubule formation, proliferation and migration).We also measured: i)mitochondrial membrane potential, mitochondrial content and apoptosis/necrosis ii) mitochondrial dynamics by flow cytometry and confocal microscopy. Results: Isolated cells maintained a cobblestone morphology and stained positive for endothelial markers. They showed a hyperproliferative phenotype when compared with control human pulmonary artery endothelial cell lines (HPAE): number of Ki67+cells (50.33±13.4 vs 32.5±9.5; p<0.05), and fold expansion (1.56±0.08 vs 0.8±0.05; p<0.002). Functionally, they showed reduced capacity to form tubule structures (150±44 vs 96±21; p<0.03). CEPTH cells tended to show lower rates of depolarized MMP, a decrease of mitochondrial content and lower levels of necrosis/apoptosis. Mitochondria from CTEPH patients tended to be smaller with higher circularity and less branching respect to controls. Conclusions: This study provides a novel endothelial cell line from PEA material. Cells show a hyperproliferative and apoptotic resistance phenotype with trends towards mitochondrial inactivation and apoptotic resistance. This could suggest a potential etiopathogenic basis for CTEPH. Funded by SEPAR, SOCAP, BIOTRACK-Postdoc Programme and PFIS ISCIII.

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