title: Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension.
abstract: Hypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca(2+) entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wild-type and canonical transient receptor potential (TRPC) 6(-/-) mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca(2+) concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia.
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Smith
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Voiriot
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.|3 Division of Translational and Regenerative Medicine, Department of Medicine and.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Fraidenburg
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.|3 Division of Translational and Regenerative Medicine, Department of Medicine and.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.|4 Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.|5 Department of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.|6 First Affiliated Hospital, Soochow University, Suzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Pohl
authors.affiliation: 2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tauseef
authors.affiliation: 7 Development, Aging, and Regeneration Program, Sanford-Burnham Institute for Medical Research, La Jolla, California.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.affiliation: 7 Development, Aging, and Regeneration Program, Sanford-Burnham Institute for Medical Research, La Jolla, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Ocorr
authors.affiliation: Departments of 8 Surgery.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thistlethwaite
authors.affiliation: 9 Pediatrics, and.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
authors.affiliation: 10 Medicine, University of California, San Diego, La Jolla, California; and.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Powell
authors.affiliation: Departments of 1 Medicine and.|11 Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.affiliation: 2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Dolly
authors.initials: D
authors.lastname: Mehta
authors.affiliation: Departments of 1 Medicine and.|2 Pharmacology, University of Illinois at Chicago, Chicago, Illinois.|3 Division of Translational and Regenerative Medicine, Department of Medicine and.|11 Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D014661:Vasoconstriction
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse
keywords: TRPC6; hypoxia; notch; pulmonary artery; store-operated Ca2+ entry