Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin

Xin Yun, Haiyang Jiang, Ning Lai, Jian Wang, Larissa A. Shimoda

Research output: Contribution to journalArticle

Abstract

Exposure to hypoxia induces migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), leading to vascular remodeling and contributing to the development of hypoxic pulmonary hypertension. The mechanisms controlling PASMC growth and motility are incompletely understood, although aquaporin 1 (AQP1) plays an important role. In tumor, kidney, and stem cells, AQP1 has been shown to interact with β-catenin, a dual function protein that activates the transcription of crucial target genes (i.e., c-Myc and cyclin D1) related to cell migration and proliferation. Thus the goal of this study was to examine mechanisms by which AQP1 mediates PASMC migration and proliferation, with a focus on β-catenin. Using primary rat PASMCs from resistance level pulmonary arteries infected with adenoviral constructs containing green fluorescent protein (control; AdGFP), wild-type AQP1 (AdAQP1), or AQP1 with the COOHterminal tail deleted (AdAQP1M), we demonstrated that increasing AQP1 expression upregulated β-catenin protein levels and the expression (mRNA and protein) of the known β-catenin targets c-Myc and cyclin D1. In contrast, infection with AdAQP1M had no effect on any of these variables. Using silencing approaches to reduce β-catenin levels prevented both hypoxia-and AQP1-induced migration and proliferation of PASMCs, as well as induction of c-Myc and cyclin D1 by AQP1. Thus our results indicate that elevated AQP1 levels upregulate β-catenin protein levels, via a mechanism requiring the AQP1 COOH-terminal tail, enhancing expression of β-catenin targets and promoting PASMC proliferation and migration.

Original languageEnglish (US)
Pages (from-to)L889-L898
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume313
Issue number5
DOIs
StatePublished - Nov 6 2017

Keywords

  • C-Myc
  • Growth
  • Hypoxia
  • Lin-7

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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