4.6 Article

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

Journal

FRONTIERS IN PHYSIOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2021.714785

Keywords

smooth muscle cell; pulmonary hypertension; CALHM channels; contractile-to-proliferative; phenotypical transition

Categories

Funding

  1. National Lung, Heart, and Blood Institute of the National Institutes of Health [R35 HL135807, R01 HL146764]
  2. American Heart Association Postdoctoral Fellowship [20POST35210959]

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The overexpression of calcium homeostasis modulator CALHM1/2 in proliferative pulmonary artery smooth muscle cells is associated with increased AKT/mTOR activation and cell proliferation, while downregulation of CALHM1/2 inhibits these processes. Upregulation of CALHM1/2 is observed in experimental pulmonary hypertension and in patients with pulmonary arterial hypertension, suggesting a potential role in the transition from vasoconstriction to vascular remodeling in PAH. Inhibition of CALHM channels with CGP 37157 partially reverses established experimental PH, indicating a possible target for novel therapies for PAH.
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.

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