Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension

  • Claudio Schuoler
  • Thomas J. Haider
  • Caroline Leuenberger
  • Johannes Vogel
  • Louise Ostergaard
  • Grazyna Kwapiszewska
  • Malcolm Kohler
  • Max Gassmann
  • Lars C. Huber
  • Matthias Brock
Original Contribution

Abstract

Vascular remodelling in hypoxia-induced pulmonary hypertension (PH) is driven by excessive proliferation and migration of endothelial and smooth muscle cells. The expression of aquaporin 1 (AQP1), an integral membrane water channel protein involved in the control of these processes, is tightly regulated by oxygen levels. The role of AQP1 in the pathogenesis of PH, however, has not been directly addressed so far. This study was designed to characterize expression and function of AQP1 in pulmonary vascular cells from human arteries and in the mouse model of hypoxia-induced PH. Exposure of human pulmonary vascular cells to hypoxia significantly induced the expression of AQP1. Similarly, levels of AQP1 were found to be upregulated in lungs of mice with hypoxia-induced PH. The functional role of AQP1 was further tested in human pulmonary artery smooth muscle cells demonstrating that depletion of AQP1 reduced proliferation, the migratory potential, and, conversely, increased apoptosis of these cells. This effect was associated with higher expression of the tumour suppressor gene p53. Using the mouse model of hypoxia-induced PH, application of GapmeR inhibitors targeting AQP1 abated the hypoxia-induced upregulation of AQP1 and, of note, reversed PH by decreasing both right ventricular pressure and hypertrophy back to the levels of control mice. Our data suggest an important functional role of AQP1 in the pathobiology of hypoxia-induced PH. These results offer novel insights in our pathogenetic understanding of the disease and propose AQP1 as potential therapeutic in vivo target.

Keywords

Aquaporin 1 Pulmonary hypertension Hypoxia Proliferation Vascular remodelling 

Supplementary material

395_2017_620_MOESM1_ESM.pdf (19.7 mb)
Supplementary material 1 (PDF 20122 kb)
395_2017_620_MOESM2_ESM.pdf (94 kb)
Supplementary material 2 (PDF 93 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Claudio Schuoler
    • 1
    • 2
    • 3
  • Thomas J. Haider
    • 1
    • 2
  • Caroline Leuenberger
    • 2
    • 3
  • Johannes Vogel
    • 1
  • Louise Ostergaard
    • 1
    • 2
  • Grazyna Kwapiszewska
    • 4
  • Malcolm Kohler
    • 2
    • 3
  • Max Gassmann
    • 1
    • 2
  • Lars C. Huber
    • 3
  • Matthias Brock
    • 3
  1. 1.Institute of Veterinary Physiology, Vetsuisse FacultyUniversity of ZurichZurichSwitzerland
  2. 2.Zurich Center for Integrative Human Physiology (ZIHP)University of ZurichZurichSwitzerland
  3. 3.Division of PulmonologyUniversity Hospital Zurich, University of ZurichZurichSwitzerland
  4. 4.Ludwig Boltzmann Institute for Lung Vascular ResearchGrazAustria

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