Na+, HCO3--cotransporter NBCn1 increases pHi gradients, filopodia, and migration of smooth muscle cells and promotes arterial remodelling
Na+, HCO3--cotransporter NBCn1 increases pHi gradients, filopodia, and migration of smooth muscle cells and promotes arterial remodelling
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DOI：
10.1093/cvr/cvw079
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发表时间：
2016-08-01
影响因子：
10.8
通讯作者：
Aalkjaer, Christian
中科院分区：
文献类型：
--
作者：
Boedtkjer, Ebbe;Bentzon, Jacob F.;Aalkjaer, Christian
目的动脉重塑可导致管腔狭窄和血流阻塞。我们测试的假设，即细胞酸碱运输促进血管平滑肌细胞（VSMCs）的增殖和迁移，并增强重塑的管道artery.Methods和结果Na+，HCO 3-cotransporter通过NBCn 1（Slc 4a 7）介导净酸挤出和控制稳态细胞内pH值（pH（i））在VSMCs的小鼠颈动脉和主动脉外植体。颈动脉在体内部分或完全结扎后会发生肥大性向内重塑，但与野生型小鼠相比，NBCn 1基因敲除小鼠的动脉中膜面积和厚度增加以及管腔直径减少。在存在CO2/HCO 3的情况下，在野生型而非NBCn 1敲除小鼠的原代外植体中，沿着VSMC迁移轴存在pH（i）梯度（类似于0.2单位量级）。NBCn 1的敲除或药理学抑制也减少了丝状伪足，并降低了刮伤后VSMC迁移的初始速率。干预措施，以减少H+-缓冲液的流动性（省略CO2/HCO 3-或抑制碳酸酐酶）重建轴向pHi梯度，丝状伪足，并在NBCn 1基因敲除小鼠的外植体迁移率。CO2/HCO 3-的省略也降低了全球pHi和抑制增殖的原代explots.Conclusion在生理条件下（即与CO2/HCO 3-存在），NBCn 1介导的HCO 3-摄取提高VSMC pHi和促进丝状伪足，VSMC迁移，和肥大向内重塑。我们认为颈动脉结扎后，轴向pHi梯度增强VSMC迁移，而整体酸化抑制VSMC增殖和中膜肥大。这些发现支持酸碱转运的关键作用，特别是通过NBCn 1，闭塞性动脉疾病的发展。
Aims Arterial remodelling can cause luminal narrowing and obstruct blood flow. We tested the hypothesis that cellular acidbase transport facilitates proliferation and migration of vascular smooth muscle cells (VSMCs) and enhances remodelling of conduit arteries.Methods and results Na+, HCO3--cotransport via NBCn1 (Slc4a7) mediates net acid extrusion and controls steady-state intracellular pH (pH(i)) 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 CO2/HCO3- present, gradients for pH(i) (similar to 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 CO2/HCO3- or inhibition of carbonic anhydrases) re-establish axial pHi gradients, filopodia, and migration rates in explants from NBCn1 knock-out mice. The omission of CO2/HCO3- also lowers global pHi and inhibits proliferation in primary explants.Conclusion Under physiological conditions (i.e. with CO2/HCO3- present), NBCn1-mediated HCO3- 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.