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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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.714785/full |
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| author | Marisela Rodriguez Marisela Rodriguez Jiyuan Chen Jiyuan Chen Pritesh P. Jain Aleksandra Babicheva Mingmei Xiong Mingmei Xiong Jifeng Li Jifeng Li Ning Lai Ning Lai Tengteng Zhao Moises Hernandez Angela Balistrieri Sophia Parmisano Tatum Simonson Ellen Breen Daniela Valdez-Jasso Patricia A. Thistlethwaite John Y. -J. Shyy Jian Wang Jian Wang Joe G. N. Garcia Ayako Makino Jason X. -J. Yuan |
| author_facet | Marisela Rodriguez Marisela Rodriguez Jiyuan Chen Jiyuan Chen Pritesh P. Jain Aleksandra Babicheva Mingmei Xiong Mingmei Xiong Jifeng Li Jifeng Li Ning Lai Ning Lai Tengteng Zhao Moises Hernandez Angela Balistrieri Sophia Parmisano Tatum Simonson Ellen Breen Daniela Valdez-Jasso Patricia A. Thistlethwaite John Y. -J. Shyy Jian Wang Jian Wang Joe G. N. Garcia Ayako Makino Jason X. -J. Yuan |
| author_sort | Marisela Rodriguez |
| collection | DOAJ |
| 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 Ca2+ concentration [(Ca2+)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 Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, 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. Ca2+ 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. |
| first_indexed | 2024-12-17T01:20:58Z |
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| id | doaj.art-1995a8a050974260b9221a472c8505e7 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-17T01:20:58Z |
| publishDate | 2021-08-01 |
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| series | Frontiers in Physiology |
| spelling | doaj.art-1995a8a050974260b9221a472c8505e72022-12-21T22:08:50ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-08-011210.3389/fphys.2021.714785714785Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle CellsMarisela Rodriguez0Marisela Rodriguez1Jiyuan Chen2Jiyuan Chen3Pritesh P. Jain4Aleksandra Babicheva5Mingmei Xiong6Mingmei Xiong7Jifeng Li8Jifeng Li9Ning Lai10Ning Lai11Tengteng Zhao12Moises Hernandez13Angela Balistrieri14Sophia Parmisano15Tatum Simonson16Ellen Breen17Daniela Valdez-Jasso18Patricia A. Thistlethwaite19John Y. -J. Shyy20Jian Wang21Jian Wang22Joe G. N. Garcia23Ayako Makino24Jason X. -J. Yuan25Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesDepartment of Pediatrics, Tucson, AZ, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesState Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesState Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesBeijing Chaoyang Hospital, Capital Medical University, Beijing, ChinaSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesState Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesDivision of Cardiothoracic Surgery, Department of Surgery, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesDepartment of Bioengineering, University of California, San Diego, La Jolla, CA, United StatesDivision of Cardiothoracic Surgery, Department of Surgery, La Jolla, CA, United StatesDivision of Cardiovascular Medicine, Department of Medicine, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesState Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Medicine, The University of Arizona, Tucson, AZ, United StatesDivision of Endocrinology and Metabolism, La Jolla, CA, United StatesSection of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United StatesExcessive 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 Ca2+ concentration [(Ca2+)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 Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, 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. Ca2+ 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.https://www.frontiersin.org/articles/10.3389/fphys.2021.714785/fullsmooth muscle cellpulmonary hypertensionCALHM channelscontractile-to-proliferativephenotypical transition |
| spellingShingle | Marisela Rodriguez Marisela Rodriguez Jiyuan Chen Jiyuan Chen Pritesh P. Jain Aleksandra Babicheva Mingmei Xiong Mingmei Xiong Jifeng Li Jifeng Li Ning Lai Ning Lai Tengteng Zhao Moises Hernandez Angela Balistrieri Sophia Parmisano Tatum Simonson Ellen Breen Daniela Valdez-Jasso Patricia A. Thistlethwaite John Y. -J. Shyy Jian Wang Jian Wang Joe G. N. Garcia Ayako Makino Jason X. -J. Yuan Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells Frontiers in Physiology smooth muscle cell pulmonary hypertension CALHM channels contractile-to-proliferative phenotypical transition |
| 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 | smooth muscle cell pulmonary hypertension CALHM channels contractile-to-proliferative phenotypical transition |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.714785/full |
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