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

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.

Downregulation of the S1P Transporter Spinster Homology Protein 2 (Spns2) Exerts an Anti-Fibrotic and Anti-Inflammatory Effect in Human Renal Proximal Tubular Epithelial Cells

“…A similar regulation was also seen on the protein level detected by Western blotting. AQP1 has been described as a 28 kDa protein that upon glycosylation appears in two higher molecular forms of 38–50 kDa and 55–70 kDa [ 35 , 36 , 37 ]. In HK2 cells, AQP1 ran as exclusively glycosylated forms of 38 kDa and 70 kDa with no detectable unglycosylated form ( Figure 9 B).…”

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

“…Thus, approaches that maintain or restore pulmonary endothelial function could offer new therapeutic directions in PAH. Conversely, AQP1 inhibition in pulmonary artery smooth muscle cells ameliorated hypoxia-induced pulmonary hypertension in mice 33 , suggesting that further studies are required to determine the key cell type impacted by AQP1 mutations in human PAH, and the functional impact of these AQP1 variants on water transport. The demonstration of familial segregation of AQP1 variants with PAH provides further support for the potentially causal role of these mutations in disease.…”

Molecular genetic framework underlying pulmonary arterial hypertension

“…Expression of AQP1, which encodes the plasma membrane water channel aquaporin 1, is integral to the maintenance of vascular tone 72 . Animal studies indicate that abrogation of aquaporin 1 in PASMCs results in an attenuation of clinical features in hypoxia-induced PAH, providing the potential for targeted development of therapeutic options 73 . Aqp1-null mice have impaired endothelial cell migration and angiogenesis 74 .…”