Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Building 1170, DK-8000 Aarhus C, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark.
Cardiovasc Res. 2016 Aug 1;111(3):227-39. doi: 10.1093/cvr/cvw079. Epub 2016 Apr 13.
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.
动脉重塑可导致管腔变窄并阻碍血流。我们检验了这样一个假设，即细胞酸碱转运促进血管平滑肌细胞（VSMC）的增殖和迁移，并增强了输送动脉的重塑。
通过 NBCn1（Slc4a7）介导的[Formula: see text]-共转运实现净酸外排，并控制小鼠颈动脉和原代主动脉外植体中 VSMC 的稳态细胞内 pH（pHi）。在体内，颈动脉对部分或完全结扎会发生向心性肥厚重塑，但与野生型小鼠相比，NBCn1 敲除小鼠的动脉中，中层面积和厚度的增加以及管腔直径的减少均受到抑制。在存在[Formula: see text]的情况下，野生型而非 NBCn1 敲除小鼠的原代外植体中，VSMC 迁移的轴线上存在 pHi （约 0.2 个单位幅度）梯度。敲除 NBCn1 或药理学抑制 NBCn1 也会减少丝状伪足并降低划痕损伤后 VSMC 迁移的初始速率。降低 H（+）-缓冲剂流动性的干预措施（省略[Formula: see text]或抑制碳酸酐酶）在外植体中重建 NBCn1 敲除小鼠的轴 pHi 梯度、丝状伪足和迁移率。省略[Formula: see text]也会降低全局 pHi 并抑制原代外植体中的增殖。
在生理条件下（即存在[Formula: see text]），NBCn1 介导的[Formula: see text]摄取会升高 VSMC pHi 并促进丝状伪足、VSMC 迁移和向心性肥厚重塑。我们提出，轴向 pHi 梯度增强了 VSMC 迁移，而全局酸化抑制了颈动脉结扎后的 VSMC 增殖和中层肥大。这些发现支持酸碱转运，特别是通过 NBCn1，在闭塞性动脉疾病发展中的关键作用。
