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Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PA...

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Autores principales: Rodriguez, Marisela, Chen, Jiyuan, Jain, Pritesh P., Babicheva, Aleksandra, Xiong, Mingmei, Li, Jifeng, Lai, Ning, Zhao, Tengteng, Hernandez, Moises, Balistrieri, Angela, Parmisano, Sophia, Simonson, Tatum, Breen, Ellen, Valdez-Jasso, Daniela, Thistlethwaite, Patricia A., Shyy, John Y. -J., Wang, Jian, Garcia, Joe G. N., Makino, Ayako, Yuan, Jason X. -J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364962/
https://www.ncbi.nlm.nih.gov/pubmed/34408668
http://dx.doi.org/10.3389/fphys.2021.714785
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author Rodriguez, Marisela
Chen, Jiyuan
Jain, Pritesh P.
Babicheva, Aleksandra
Xiong, Mingmei
Li, Jifeng
Lai, Ning
Zhao, Tengteng
Hernandez, Moises
Balistrieri, Angela
Parmisano, Sophia
Simonson, Tatum
Breen, Ellen
Valdez-Jasso, Daniela
Thistlethwaite, Patricia A.
Shyy, John Y. -J.
Wang, Jian
Garcia, Joe G. N.
Makino, Ayako
Yuan, Jason X. -J.
author_facet Rodriguez, Marisela
Chen, Jiyuan
Jain, Pritesh P.
Babicheva, Aleksandra
Xiong, Mingmei
Li, Jifeng
Lai, Ning
Zhao, Tengteng
Hernandez, Moises
Balistrieri, Angela
Parmisano, Sophia
Simonson, Tatum
Breen, Ellen
Valdez-Jasso, Daniela
Thistlethwaite, Patricia A.
Shyy, John Y. -J.
Wang, Jian
Garcia, Joe G. N.
Makino, Ayako
Yuan, Jason X. -J.
author_sort Rodriguez, Marisela
collection PubMed
description Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca(2+) concentration [(Ca(2+))(cyt)] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca(2+) (and ATP) channel that is allosterically regulated by voltage and extracellular Ca(2+), is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca(2+) influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH.
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spelling pubmed-83649622021-08-17 Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells Rodriguez, Marisela Chen, Jiyuan Jain, Pritesh P. Babicheva, Aleksandra Xiong, Mingmei Li, Jifeng Lai, Ning Zhao, Tengteng Hernandez, Moises Balistrieri, Angela Parmisano, Sophia Simonson, Tatum Breen, Ellen Valdez-Jasso, Daniela Thistlethwaite, Patricia A. Shyy, John Y. -J. Wang, Jian Garcia, Joe G. N. Makino, Ayako Yuan, Jason X. -J. Front Physiol Physiology Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca(2+) concentration [(Ca(2+))(cyt)] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca(2+) (and ATP) channel that is allosterically regulated by voltage and extracellular Ca(2+), is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca(2+) influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH. Frontiers Media S.A. 2021-08-02 /pmc/articles/PMC8364962/ /pubmed/34408668 http://dx.doi.org/10.3389/fphys.2021.714785 Text en Copyright © 2021 Rodriguez, Chen, Jain, Babicheva, Xiong, Li, Lai, Zhao, Hernandez, Balistrieri, Parmisano, Simonson, Breen, Valdez-Jasso, Thistlethwaite, Shyy, Wang, Garcia, Makino and Yuan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Rodriguez, Marisela
Chen, Jiyuan
Jain, Pritesh P.
Babicheva, Aleksandra
Xiong, Mingmei
Li, Jifeng
Lai, Ning
Zhao, Tengteng
Hernandez, Moises
Balistrieri, Angela
Parmisano, Sophia
Simonson, Tatum
Breen, Ellen
Valdez-Jasso, Daniela
Thistlethwaite, Patricia A.
Shyy, John Y. -J.
Wang, Jian
Garcia, Joe G. N.
Makino, Ayako
Yuan, Jason X. -J.
Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells
title Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells
title_full Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells
title_fullStr Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells
title_full_unstemmed Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells
title_short Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells
title_sort upregulation of calcium homeostasis modulators in contractile-to-proliferative phenotypical transition of pulmonary arterial smooth muscle cells
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364962/
https://www.ncbi.nlm.nih.gov/pubmed/34408668
http://dx.doi.org/10.3389/fphys.2021.714785
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