The Aquaporin 1 C-Terminal Tail Is Required for Migration and Growth of Pulmonary Arterial Myocytes

Lai, Ning; Lade, Julie M.; Leggett, Kyle; Xing, Yun; Baksh, Syeda; Chau, Eric; Crow, Michael T.; Sidhaye, Venkataramana K.; Wang, Jian; Shimoda, Larissa A.

doi:10.1165/rcmb.2013-0374oc

Cited by 17 publications

(31 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In detail, rat pulmonary artery smooth muscle cells exposed to hypoxia selectively increased AQP1 protein levels and, in turn, migration. Silencing of AQP1 via siRNA prevented the hypoxia-induced migration in these cells [13,14]. Our initial experiments confirmed these findings by showing that the levels of AQP1 are increased by hypoxia in pulmonary artery smooth muscle cells.…”

Section: Discussionsupporting

confidence: 77%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 77%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…43 Direct effects of hypoxia on PASMCs are also likely to play a role in vascular remodeling. For example, cells exposed to hypoxia ex vivo or derived from chronically hypoxic animals exhibit increases in both migration and proliferation, [53][54][55][56] and both K + channel activity and [Ca 2+ ] i are likely to play a role. Agents that activate and/or increase expression of K + channels, including the steroid hormone dehydroepiandrosterone and the metabolic modulator dichloroacetate, reduced remodeling in chronically hypoxic rats, 46,57,58 likely because increased intracellular K + confers resistance to apoptosis.…”

Section: Mechanisms Of Hph: Lessons From Animal Modelsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

View full text Add to dashboard Cite

Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca 2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.Keywords: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

show abstract

“…AQP1 has been shown to facilitate cell migration (7), cell proliferation (8), and angiogenesis (9). One recent study found an interaction between AQP1 and b-catenin, a transcription cofactor with T-cell factor/lymphoid enhancer factor (TCF/LEF) in the Wnt signal pathway.…”

mentioning

confidence: 99%

Aquaporin‐1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling

Wang

Sun

et al. 2015

FASEB j.

View full text Add to dashboard Cite

Water channel aquaporin-1 (AQP1) is expressed at epithelial cell plasma membranes in renal proximal tubules and thin descending limb of Henle. Recently, AQP1 was reported to interact with b-catenin. Here we investigated the relationship between AQP1 and Wnt signaling in in vitro and in vivo models of autosomal dominant polycystic kidney disease (PKD). AQP1 overexpression decreased b-catenin and cyclinD1 expression, suggesting down-regulation of Wnt signaling, and coimmunoprecipitation showed AQP1 interaction with bcatenin, glycogen synthase kinase 3b, LRP6, and Axin1. AQP1 inhibited cyst development and promoted branching in matrix-grown MDCK cells. In embryonic kidney cultures, AQP1 deletion increased cyst development by up to ∼40%. Kidney size and cyst number were significantly greater in AQP1-null PKD mice than in AQP1-expressing PKD mice, with the difference mainly attributed to a greater number of proximal tubule cysts. Biochemical analysis revealed decreased b-catenin phosphorylation and increased b-catenin expression in AQP1-null PKD mice, suggesting enhanced Wnt signaling. These results implicate AQP1 as a novel determinant in renal cyst development that may involve inhibition of Wnt signaling by an AQP1-macromolecular signaling

show abstract

The Aquaporin 1 C-Terminal Tail Is Required for Migration and Growth of Pulmonary Arterial Myocytes

Cited by 17 publications

References 37 publications

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

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

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Aquaporin‐1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling

Contact Info

Product

Resources

About