Hypoxia‐induced proliferation and migration in pulmonary arterial smooth muscle cells requires β‐catenin.

Abstract

Exposure to hypoxia causes proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) in the distal vasculature, leading to structural remodeling of these arteries and contributing to the pathogenesis of pulmonary hypertension. In past studies, we showed that expression of the water channel, aquaporin 1 (AQP1), was upregulated by both in vivo and in vitro exposure to hypoxia, and that this channel mediated PASMC proliferation and migration. The effects of AQP1 were independent of channel water transport, but were associated with increased expression of β‐catenin, a dual function protein that is involved in the Wnt signaling pathway. β‐catenin activates transcription of genes involved in cell growth and survival and regulates the coordination of cell‐cell adhesion. Thus, we explored whether β‐catenin was required for hypoxia‐induced PASMC migration and proliferation. Primary cultures of rat PASMCs were harvested from distal pulmonary arteries and exposed to in vitro hypoxia (4% O2 ‐ 5% CO2) or control conditions. Proliferation and migration were measured using BrdU incorporation and transwell filters, respectively. Exposure to hypoxia for 24–72 h increased PASMC migration and proliferation and β‐catenin protein, but not mRNA, levels. Silencing β‐catenin in PASMCs had no significant effect on cell function under control conditions, but prevented hypoxia‐induced proliferation and migration. Based on our findings, we conclude that increases in β‐catenin protein stability/synthesis, perhaps mediated by AQP1, are crucial for hypoxia‐induced PASMC proliferation and migration.Support or Funding InformationThis work was funded by HL‐07963 and AHA0755479.