title: Flow shear stress enhances intracellular Ca2+ signaling in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension.
abstract: An increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for pulmonary arterial medial hypertrophy in patients with idiopathic pulmonary arterial hypertension (IPAH). Vascular smooth muscle cells (SMC) sense the blood flow shear stress through interstitial fluid driven by pressure or direct exposure to blood flow in case of endothelial injury. Mechanical stimulus can increase [Ca(2+)]cyt. Here we report that flow shear stress raised [Ca(2+)]cyt in PASMC, while the shear stress-mediated rise in [Ca(2+)]cyt and the protein expression level of TRPM7 and TRPV4 channels were significantly greater in IPAH-PASMC than in normal PASMC. Blockade of TRPM7 by 2-APB or TRPV4 by Ruthenium red inhibited shear stress-induced rise in [Ca(2+)]cyt in normal and IPAH-PASMC, while activation of TRPM7 by bradykinin or TRPV4 by 4αPDD induced greater increase in [Ca(2+)]cyt in IPAH-PASMC than in normal PASMC. The bradykinin-mediated activation of TRPM7 also led to a greater increase in [Mg(2+)]cyt in IPAH-PASMC than in normal PASMC. Knockdown of TRPM7 and TRPV4 by siRNA significantly attenuated the shear stress-mediated [Ca(2+)]cyt increases in normal and IPAH-PASMC. In conclusion, upregulated mechanosensitive channels (e.g., TRPM7, TRPV4, TRPC6) contribute to the enhanced [Ca(2+)]cyt increase induced by shear stress in PASMC from IPAH patients. Blockade of the mechanosensitive cation channels may represent a novel therapeutic approach for relieving elevated [Ca(2+)]cyt in PASMC and thereby inhibiting sustained pulmonary vasoconstriction and pulmonary vascular remodeling in patients with IPAH.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine and Physiology, University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.affiliation: Kinjo Gakuin University School of Pharmacy, Nagoya, Japan; and.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.affiliation: Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine and Physiology, University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Ayon
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine and Physiology, University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine and Physiology, University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine and Physiology, University of Arizona College of Medicine, Tucson, Arizona; jasonyuan@email.arizona.edu.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D062186:Arterial Pressure; D020013:Calcium Signaling / Q000187:drug effects; D016022:Case-Control Studies; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008274:Magnesium / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D034622:RNA Interference; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D050053:TRPM Cation Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D049990:Membrane Transport Modulators; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D008274:Magnesium
keywords: TRPM7; TRPV4; mechanosensitive channel; shear stress