Abstract
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by exuberant vascular remodeling leading to elevated pulmonary arterial pressure, maladaptive right ventricular remodeling, and eventual death. The factors controlling pulmonary arterial smooth muscle cell (PASMC) and endothelial cell hyperplasia and migration, hallmark features of the vascular remodeling observed in PAH, remain poorly understood. We previously demonstrated that hypoxia upregulates the expression of aquaporin 1 (AQP1), a water channel, in PASMCs, and that this upregulation was required for hypoxia-induced migration and proliferation. However, whether the same is true in a model of severe PAH and in pulmonary microvascular endothelial cells (MVECs) is unknown. In this study, we used the SU5416 plus hypoxia (SuHx) rat model of severe pulmonary hypertension, which mimics many of the features of human PAH, to determine whether AQP1 levels were altered in PASMCs and MVECs and contributed to a hyperproliferative/hypermigratory phenotype. Rats received a single injection of SU5416 (20 mg/kg) and then were placed in 10% O2 for 3 weeks, followed by a return to normoxic conditions for an additional 2 weeks. We found that AQP1 protein levels were increased in both PASMCs and MVECs from SuHx rats, even in the absence of sustained hypoxic exposure, and that in MVECs, the increase in protein expression was associated with upregulation of AQP1 mRNA levels. Silencing of AQP1 had no significant effect on PASMCs from control animals but normalized enhanced migration and proliferation observed in cells from SuHx rats. Loss of AQP1 also reduced migration and proliferation in MVECs from SuHx rats. Finally, augmenting AQP1 levels in MVECs from control rats using forced expression was sufficient to increase migration and proliferation. These results demonstrate a key role for enhanced AQP1 expression in mediating abnormal migration and proliferation in pulmonary vascular cells from a rodent model that reflects many of the features of human PAH.
Highlights
MATERIALS AND METHODSPulmonary hypertension (PH) is a devastating, progressive condition of varying etiology leading to eventual right heart failure
We explored the role of aquaporin 1 (AQP1) in modulating pulmonary vascular cell migration and proliferation in a severe model of PH that captures many of the features of human Pulmonary arterial hypertension (PAH)
We found that both pulmonary arterial smooth muscle cell (PASMC) and microvascular endothelial cells (MVECs) from SU5416 plus hypoxia (SuHx) rats have enhanced expression of AQP1 that was associated with a more robust migratory and proliferative phenotype
Summary
Pulmonary hypertension (PH) is a devastating, progressive condition of varying etiology leading to eventual right heart failure. We demonstrated that hypoxia upregulates the protein expression of the water channel, aquaporin 1 (AQP1), in pulmonary arterial smooth muscle cells (PASMCs) and identified a role for this protein in mediating proliferation and migration in response to hypoxia (Leggett et al, 2012). Following this initial study, other labs confirmed the role of AQP1 in governing PASMC growth during hypoxia and showed that targeting AQP1 in vivo reduced the development of hypoxia-induced PH in rodents (Schuoler et al, 2017; Liu et al, 2019). The current study tested the hypothesis that AQP1 is upregulated in PASMCs and MVECs from the SuHx rat model and contributes to the abnormal growth and migration observed in these cells
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