title: Na+, HCO3--cotransporter NBCn1 increases pHi gradients, filopodia, and migration of smooth muscle cells and promotes arterial remodelling.
abstract: Arterial remodelling can cause luminal narrowing and obstruct blood flow. We tested the hypothesis that cellular acid-base transport facilitates proliferation and migration of vascular smooth muscle cells (VSMCs) and enhances remodelling of conduit arteries.
  
  
  
  [Formula: see text]-cotransport via NBCn1 (Slc4a7) mediates net acid extrusion and controls steady-state intracellular pH (pHi) in VSMCs of mouse carotid arteries and primary aortic explants. Carotid arteries undergo hypertrophic inward remodelling in response to partial or complete ligation in vivo, but the increase in media area and thickness and reduction in lumen diameter are attenuated in arteries from NBCn1 knock-out compared with wild-type mice. With [Formula: see text] present, gradients for pHi (∼0.2 units magnitude) exist along the axis of VSMC migration in primary explants from wild-type but not NBCn1 knock-out mice. Knock-out or pharmacological inhibition of NBCn1 also reduces filopodia and lowers initial rates of VSMC migration after scratch-wound infliction. Interventions to reduce H(+)-buffer mobility (omission of [Formula: see text] or inhibition of carbonic anhydrases) re-establish axial pHi gradients, filopodia, and migration rates in explants from NBCn1 knock-out mice. The omission of [Formula: see text] also lowers global pHi and inhibits proliferation in primary explants.
  
  
  
  Under physiological conditions (i.e. with [Formula: see text] present), NBCn1-mediated [Formula: see text] uptake raises VSMC pHi and promotes filopodia, VSMC migration, and hypertrophic inward remodelling. We propose that axial pHi gradients enhance VSMC migration whereas global acidification inhibits VSMC proliferation and media hypertrophy after carotid artery ligation. These findings support a key role of acid-base transport, particularly via NBCn1, for development of occlusive artery disease.
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Building 1170, DK-8000 Aarhus C, Denmark eb@biomed.au.dk.
authors.forename: Ebbe
authors.initials: E
authors.lastname: Boedtkjer
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Bentzon
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Building 1170, DK-8000 Aarhus C, Denmark.
authors.forename: Vibeke S
authors.initials: VS
authors.lastname: Dam
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Building 1170, DK-8000 Aarhus C, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005838:Genotype; D006863:Hydrogen-Ion Concentration; D006984:Hypertrophy; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D027982:Sodium-Bicarbonate Symporters / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D001639:Bicarbonates; D012333:RNA, Messenger; C498904:Slc4a7 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D002245:Carbon Dioxide; D012964:Sodium
keywords: Blood flow; Carotid arteries; Remodelling; Restenosis; Smooth muscle