TY - JOUR
T1 - Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension
AU - Tura-Ceide, Olga
AU - Smolders, Valérie F.E.D.
AU - Aventin, Núria
AU - Morén, Constanza
AU - Guitart-Mampel, Mariona
AU - Blanco, Isabel
AU - Piccari, Lucilla
AU - Osorio, Jeisson
AU - Rodríguez, Cristina
AU - Rigol, Montserrat
AU - Solanes, Núria
AU - Malandrino, Andrea
AU - Kurakula, Kondababu
AU - Goumans, Marie Jose
AU - Quax, Paul H.A.
AU - Peinado, Victor I.
AU - Castellà, Manuel
AU - Barberà, Joan Albert
N1 - Funding Information: This research was supported by the funding from Marie Curie Post-Doctoral Fellowship Award BIOTRACK: IDIBAPS, a Miguel Servet Grant from the Instituto de Salud Carlos III (CP17/00114), the European Commission Horizon 2020 research and innovation program under the MOGLYNET H2020-MSCA-ITN-EJD Grant (Agreement No 675527), Spanish Society of Respiratory Medicine (SEPAR 2013), Catalan Society of Pneumology (SOCAP 2015), Fundación Contra la Hipertensión Pulmonar (FCHP) and research Grants PI15/00582 and PI18/00960 from the Institute of Health Carlos III, Spain. Cofunding was provided by the Fondo Europeo de Desarrollo Regional (FEDER); “Una manera de hacer Europa”. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Pulmonary endarterectomy (PEA) resected material offers a unique opportunity to develop an in vitro endothelial cell model of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to comprehensively analyze the endothelial function, molecular signature, and mitochondrial profile of CTEPH-derived endothelial cells to better understand the pathophysiological mechanisms of endothelial dysfunction behind CTEPH, and to identify potential novel targets for the prevention and treatment of the disease. Isolated cells from specimens obtained at PEA (CTEPH-EC), were characterized based on morphology, phenotype, and functional analyses (in vitro and in vivo tubule formation, proliferation, apoptosis, and migration). Mitochondrial content, morphology, and dynamics, as well as high-resolution respirometry and oxidative stress, were also studied. CTEPH-EC displayed a hyperproliferative phenotype with an increase expression of adhesion molecules and a decreased apoptosis, eNOS activity, migration capacity and reduced angiogenic capacity in vitro and in vivo compared to healthy endothelial cells. CTEPH-EC presented altered mitochondrial dynamics, increased mitochondrial respiration and an unbalanced production of reactive oxygen species and antioxidants. Our study is the foremost comprehensive investigation of CTEPH-EC. Modulation of redox, mitochondrial homeostasis and adhesion molecule overexpression arise as novel targets and biomarkers in CTEPH.
AB - Pulmonary endarterectomy (PEA) resected material offers a unique opportunity to develop an in vitro endothelial cell model of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to comprehensively analyze the endothelial function, molecular signature, and mitochondrial profile of CTEPH-derived endothelial cells to better understand the pathophysiological mechanisms of endothelial dysfunction behind CTEPH, and to identify potential novel targets for the prevention and treatment of the disease. Isolated cells from specimens obtained at PEA (CTEPH-EC), were characterized based on morphology, phenotype, and functional analyses (in vitro and in vivo tubule formation, proliferation, apoptosis, and migration). Mitochondrial content, morphology, and dynamics, as well as high-resolution respirometry and oxidative stress, were also studied. CTEPH-EC displayed a hyperproliferative phenotype with an increase expression of adhesion molecules and a decreased apoptosis, eNOS activity, migration capacity and reduced angiogenic capacity in vitro and in vivo compared to healthy endothelial cells. CTEPH-EC presented altered mitochondrial dynamics, increased mitochondrial respiration and an unbalanced production of reactive oxygen species and antioxidants. Our study is the foremost comprehensive investigation of CTEPH-EC. Modulation of redox, mitochondrial homeostasis and adhesion molecule overexpression arise as novel targets and biomarkers in CTEPH.
KW - Apoptosis
KW - Case-Control Studies
KW - Chronic Disease
KW - Endothelium, Vascular/cytology
KW - Female
KW - Humans
KW - Hypertension, Pulmonary/pathology
KW - Male
KW - Middle Aged
KW - Mitochondria/pathology
KW - Oxidative Stress
KW - Pulmonary Artery/cytology
KW - Pulmonary Embolism/pathology
UR - http://www.scopus.com/inward/record.url?scp=85115391842&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41598-021-98320-1
DO - https://doi.org/10.1038/s41598-021-98320-1
M3 - Article
C2 - 34552142
SN - 2045-2322
VL - 11
SP - 18797
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 18797
ER -