Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized clots obstructing the pulmonary arteries. Pulmonary endarterectomy (PEA) is the standard treatment, but in cases of inoperability, Riociguat, a soluble guanylate cyclase (sGC) stimulator...

Descripción completa

Detalles Bibliográficos
Autores: Poyatos Dorado, Paula, Tura Ceide, Olga, Peinado Cabré, Víctor Ivo, Blanco Vich, Isabel, Osorio, Jeisson, Yuan, Shuai, Ramírez, Ana M., Castellà Pericàs, Manuel, Rigol Muxart, Montserrat, Solanes, Núria, Straub, Adam C, Barberà i Mir, Joan Albert
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/224670
Acceso en línea:https://hdl.handle.net/2445/224670
Access Level:acceso abierto
Palabra clave:Hipertensió pulmonar
Endoteli
Medicaments
Pulmonary hypertension
Endothelium
Drugs
id ES_f80cf846cb6f810d5080bcbd98d1a7dd
oai_identifier_str oai:diposit.ub.edu:2445/224670
network_acronym_str ES
network_name_str España
repository_id_str
spelling Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cellsPoyatos Dorado, PaulaTura Ceide, OlgaPeinado Cabré, Víctor IvoBlanco Vich, IsabelOsorio, JeissonYuan, ShuaiRamírez, Ana M.Castellà Pericàs, ManuelRigol Muxart, MontserratSolanes, NúriaStraub, Adam CBarberà i Mir, Joan AlbertHipertensió pulmonarEndoteliMedicamentsPulmonary hypertensionEndotheliumDrugsIntroduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized clots obstructing the pulmonary arteries. Pulmonary endarterectomy (PEA) is the standard treatment, but in cases of inoperability, Riociguat, a soluble guanylate cyclase (sGC) stimulator, is the only approved pharmacological option. Endothelial dysfunction (ED) plays a central role, with the NO/sGC/cGMP pathway being critically involved. The aim of this study is to identify the molecular pathways contributing to ED and assess the therapeutic potential of Riociguat, BAY 60-2770, and Sildenafil in reinstating vascular homeostasis. Materials and methods: Endothelial cells (ECs) were isolated from PEA specimens of individuals diagnosed with CTEPH (CTEPH-EC). ECs derived from healthy pulmonary arteries (HPAECs) were used as controls. Cells were treated with different concentrations of Riociguat, BAY-60-2770 and Sildenafil, followed by functional assays, transcriptomic, and molecular analyses. Results: The drugs used induced significant effects on endothelial cell dynamics, including decreased proliferation, increased apoptosis, and enhanced angiogenesis both in vitro and in vivo. Transcriptomic analysis followed by validation studies identified significant alterations in genes related to angiogenesis, with marked changes observed following BAY 60-2770 treatment. Dysregulation in the ERK/eNOS/PKG signaling pathway was demonstrated in CTEPH-EC compared to HPAEC at both the gene and protein level. Treatment with Riociguat and Sildenafil restored ERK/eNOS, but not PKG signaling. Conclusion: Therapeutic approaches targeting endothelial dysfunction and the NO/sGC pathway in CTEPH partially restore endothelial function, highlighting the dual action of Riociguat and Sildenafil, stimulating sGC while exerting upstream effects by enhancing eNOS signaling. These findings underscore the importance of targeted pharmacological approaches to improve patient outcomes.Elsevier Masson SAS2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/224670Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.biopha.2025.118425Biomedicine & Pharmacotherapy, 2025, vol. 190, num.118425https://doi.org/10.1016/j.biopha.2025.118425cc by (c) Poyatos Dorado, Paula et al., 2025 https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2246702026-05-27T06:46:51Z
dc.title.none.fl_str_mv Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
title Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
spellingShingle Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
Poyatos Dorado, Paula
Hipertensió pulmonar
Endoteli
Medicaments
Pulmonary hypertension
Endothelium
Drugs
title_short Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
title_full Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
title_fullStr Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
title_full_unstemmed Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
title_sort Assessing the role of endothelium-protective drugs: Functional and molecular insights into chronic thromboembolic pulmonary hypertension derived endothelial cells
dc.creator.none.fl_str_mv Poyatos Dorado, Paula
Tura Ceide, Olga
Peinado Cabré, Víctor Ivo
Blanco Vich, Isabel
Osorio, Jeisson
Yuan, Shuai
Ramírez, Ana M.
Castellà Pericàs, Manuel
Rigol Muxart, Montserrat
Solanes, Núria
Straub, Adam C
Barberà i Mir, Joan Albert
author Poyatos Dorado, Paula
author_facet Poyatos Dorado, Paula
Tura Ceide, Olga
Peinado Cabré, Víctor Ivo
Blanco Vich, Isabel
Osorio, Jeisson
Yuan, Shuai
Ramírez, Ana M.
Castellà Pericàs, Manuel
Rigol Muxart, Montserrat
Solanes, Núria
Straub, Adam C
Barberà i Mir, Joan Albert
author_role author
author2 Tura Ceide, Olga
Peinado Cabré, Víctor Ivo
Blanco Vich, Isabel
Osorio, Jeisson
Yuan, Shuai
Ramírez, Ana M.
Castellà Pericàs, Manuel
Rigol Muxart, Montserrat
Solanes, Núria
Straub, Adam C
Barberà i Mir, Joan Albert
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Hipertensió pulmonar
Endoteli
Medicaments
Pulmonary hypertension
Endothelium
Drugs
topic Hipertensió pulmonar
Endoteli
Medicaments
Pulmonary hypertension
Endothelium
Drugs
description Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized clots obstructing the pulmonary arteries. Pulmonary endarterectomy (PEA) is the standard treatment, but in cases of inoperability, Riociguat, a soluble guanylate cyclase (sGC) stimulator, is the only approved pharmacological option. Endothelial dysfunction (ED) plays a central role, with the NO/sGC/cGMP pathway being critically involved. The aim of this study is to identify the molecular pathways contributing to ED and assess the therapeutic potential of Riociguat, BAY 60-2770, and Sildenafil in reinstating vascular homeostasis. Materials and methods: Endothelial cells (ECs) were isolated from PEA specimens of individuals diagnosed with CTEPH (CTEPH-EC). ECs derived from healthy pulmonary arteries (HPAECs) were used as controls. Cells were treated with different concentrations of Riociguat, BAY-60-2770 and Sildenafil, followed by functional assays, transcriptomic, and molecular analyses. Results: The drugs used induced significant effects on endothelial cell dynamics, including decreased proliferation, increased apoptosis, and enhanced angiogenesis both in vitro and in vivo. Transcriptomic analysis followed by validation studies identified significant alterations in genes related to angiogenesis, with marked changes observed following BAY 60-2770 treatment. Dysregulation in the ERK/eNOS/PKG signaling pathway was demonstrated in CTEPH-EC compared to HPAEC at both the gene and protein level. Treatment with Riociguat and Sildenafil restored ERK/eNOS, but not PKG signaling. Conclusion: Therapeutic approaches targeting endothelial dysfunction and the NO/sGC pathway in CTEPH partially restore endothelial function, highlighting the dual action of Riociguat and Sildenafil, stimulating sGC while exerting upstream effects by enhancing eNOS signaling. These findings underscore the importance of targeted pharmacological approaches to improve patient outcomes.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/224670
url https://hdl.handle.net/2445/224670
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.biopha.2025.118425
Biomedicine & Pharmacotherapy, 2025, vol. 190, num.118425
https://doi.org/10.1016/j.biopha.2025.118425
dc.rights.none.fl_str_mv cc by (c) Poyatos Dorado, Paula et al., 2025
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Poyatos Dorado, Paula et al., 2025
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier Masson SAS
publisher.none.fl_str_mv Elsevier Masson SAS
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869424966073581568
score 15.811543

Similares en LA Referencia