title: Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype.
abstract: Pulmonary arterial hypertension (PAH) is a progressive disease that, if left untreated, eventually leads to right heart failure and death. Elevated pulmonary arterial pressure (PAP) in patients with PAH is mainly caused by an increase in pulmonary vascular resistance (PVR). Sustained vasoconstriction and excessive pulmonary vascular remodeling are two major causes for elevated PVR in patients with PAH. Excessive pulmonary vascular remodeling is mediated by increased proliferation of pulmonary arterial smooth muscle cells (PASMC) due to PASMC dedifferentiation from a contractile or quiescent phenotype to a proliferative or synthetic phenotype. Increased cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in PASMC is a key stimulus for cell proliferation and this phenotypic transition. Voltage-dependent Ca(2+) entry (VDCE) and store-operated Ca(2+) entry (SOCE) are important mechanisms for controlling [Ca(2+)]cyt. Stromal interacting molecule proteins (e.g., STIM2) and Orai2 both contribute to SOCE and we have previously shown that STIM2 and Orai2, specifically, are upregulated in PASMC from patients with idiopathic PAH and from animals with experimental pulmonary hypertension in comparison to normal controls. In this study, we show that STIM2 and Orai2 are upregulated in proliferating PASMC compared with contractile phenotype of PASMC. Additionally, a switch in Ca(2+) regulation is observed in correlation with a phenotypic transition from contractile PASMC to proliferative PASMC. PASMC in a contractile phenotype or state have increased VDCE, while in the proliferative phenotype or state PASMC have increased SOCE. The data from this study indicate that upregulation of STIM2 and Orai2 is involved in the phenotypic transition of PASMC from a contractile state to a proliferative state; the enhanced SOCE due to upregulation of STIM2 and Orai2 plays an important role in PASMC proliferation.
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, University of Illinois at Chicago, Chicago, Ilinois; Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona; and.
authors: Ruby A
authors: RA
authors: Fernandez
authors: Department of Medicine, University of Illinois at Chicago, Chicago, Ilinois;
authors: Jun
authors: J
authors: Wan
authors: Department of Medicine, University of Illinois at Chicago, Chicago, Ilinois; Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona; and.
authors: Shanshan
authors: S
authors: Song
authors: Department of Medicine, University of Illinois at Chicago, Chicago, Ilinois;
authors: Kimberly A
authors: KA
authors: Smith
authors: Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona; and.
authors: Yali
authors: Y
authors: Gu
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois;
authors: Mohammad
authors: M
authors: Tauseef
authors: Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona; and.
authors: Haiyang
authors: H
authors: Tang
authors: Department of Medicine, University of Illinois at Chicago, Chicago, Ilinois; Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
authors: Ayako
authors: A
authors: Makino
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois;
authors: Dolly
authors: D
authors: Mehta
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, University of Illinois at Chicago, Chicago, Ilinois; Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona; and Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona jasonyuan@email.arizona.edu.
authors: Jason X-J
authors: JX
authors: Yuan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D009543:Nifedipine / Q000494:pharmacology; D000071741:ORAI2 Protein; D011651:Pulmonary Artery / Q000166:cytology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071738:Stromal Interaction Molecule 2; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D000074287:TRPC6 Cation Channel; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D066253:Vascular Remodeling / Q000502:physiology*; D014655:Vascular Resistance; D014661:Vasoconstriction
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D008562:Membrane Glycoproteins; D000071741:ORAI2 Protein; C520431:Orai2 protein, mouse; D034741:RNA, Small Interfering; C525024:Stim2 protein, mouse; D000071738:Stromal Interaction Molecule 2; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D016212:Transforming Growth Factor beta; C492146:Trpc6 protein, mouse; D009543:Nifedipine; D002118:Calcium
keywords: PASMC; phenotype; pulmonary artery; store-operated calcium channel