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Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous

Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs f...

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Autores principales: Perros, Frédéric, Sentenac, Pierre, Boulate, David, Manaud, Grégoire, Kotsimbos, Tom, Lecerf, Florence, Lamrani, Lilia, Fadel, Elie, Mercier, Olaf, Londono-Vallejo, Arturo, Humbert, Marc, Eddahibi, Saadia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679125/
https://www.ncbi.nlm.nih.gov/pubmed/31336611
http://dx.doi.org/10.3390/ijms20143575
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author Perros, Frédéric
Sentenac, Pierre
Boulate, David
Manaud, Grégoire
Kotsimbos, Tom
Lecerf, Florence
Lamrani, Lilia
Fadel, Elie
Mercier, Olaf
Londono-Vallejo, Arturo
Humbert, Marc
Eddahibi, Saadia
author_facet Perros, Frédéric
Sentenac, Pierre
Boulate, David
Manaud, Grégoire
Kotsimbos, Tom
Lecerf, Florence
Lamrani, Lilia
Fadel, Elie
Mercier, Olaf
Londono-Vallejo, Arturo
Humbert, Marc
Eddahibi, Saadia
author_sort Perros, Frédéric
collection PubMed
description Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells—the defining feature of neoplasia.
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spelling pubmed-66791252019-08-19 Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous Perros, Frédéric Sentenac, Pierre Boulate, David Manaud, Grégoire Kotsimbos, Tom Lecerf, Florence Lamrani, Lilia Fadel, Elie Mercier, Olaf Londono-Vallejo, Arturo Humbert, Marc Eddahibi, Saadia Int J Mol Sci Article Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells—the defining feature of neoplasia. MDPI 2019-07-22 /pmc/articles/PMC6679125/ /pubmed/31336611 http://dx.doi.org/10.3390/ijms20143575 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Perros, Frédéric
Sentenac, Pierre
Boulate, David
Manaud, Grégoire
Kotsimbos, Tom
Lecerf, Florence
Lamrani, Lilia
Fadel, Elie
Mercier, Olaf
Londono-Vallejo, Arturo
Humbert, Marc
Eddahibi, Saadia
Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
title Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
title_full Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
title_fullStr Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
title_full_unstemmed Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
title_short Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
title_sort smooth muscle phenotype in idiopathic pulmonary hypertension: hyper-proliferative but not cancerous
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679125/
https://www.ncbi.nlm.nih.gov/pubmed/31336611
http://dx.doi.org/10.3390/ijms20143575
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