title: The Na+/H+ exchanger contributes to increased smooth muscle proliferation and migration in a rat model of pulmonary arterial hypertension.
abstract: Increased muscularity of small pulmonary vessels, involving enhanced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a key component of the vascular remodeling underlying the development of pulmonary hypertension (PH). Stimuli such as growth factors and hypoxia induce PASMC alkalinization, proliferation, and migration through upregulation of the Na(+)/H(+) exchanger (NHE), inhibition of which prevents the development of hypoxia-induced vascular remodeling and PH. We wanted to explore whether NHE was also necessary for pathologic PASMC proliferation and migration in a model of pulmonary arterial hypertension (PAH), a severe form of PH not associated with persistent hypoxia. PASMCs were isolated from rats exposed to SU5416-hypoxia (SuHx) followed by return to normoxia and from vehicle controls. We measured resting intracellular pH (pHi) and NHE activity using the pH-sensitive fluorescent dye BCECF-AM. PASMC proliferation and migration were assessed using BrdU incorporation and transwell filters, respectively. NHE activity was increased in SuHx PASMCs, although resting pHi was unchanged. SuHx PASMCs also exhibited increased proliferation and migration relative to controls, which was attenuated in the setting of pharmacologic inhibition of NHE. Our findings suggest that increased NHE activity contributes to pathologic PASMC function in the SuHx model of PAH, although this effect does not appear to be mediated by global changes in pHi homeostasis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: John C
authors.initials: JC
authors.lastname: Huetsch
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Larrain
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland lshimod1@jhmi.edu.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Shimoda
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007211:Indoles; D011758:Pyrroles; D017923:Sodium-Hydrogen Exchangers; C116890:Semaxinib
keywords: Intracellular pH; migration; proliferation; pulmonary hypertension; smooth muscle; sodium–hydrogen exchanger