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

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 beta-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 beta-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 beta-catenin protein levels and the expression (mRNA and protein) of the known beta-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 beta-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 beta-catenin protein levels, via a mechanism requiring the AQP1 COOH-terminal tail, enhancing expression of beta-catenin targets and promoting PASMC proliferation and migration.