Large-conductance Ca(2 +)-activated K(+) channel β1-subunit maintains the contractile phenotype of vascular smooth muscle cells.
Large-conductance Ca(2 +)-activated K(+) channel β1-subunit maintains the contractile phenotype of vascular smooth muscle cells.
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DOI：
10.3389/fcvm.2022.1062695
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发表时间：
2022
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
血管平滑肌细胞(VSMCs)的表型转换在血管疾病的发生发展过程中起着非常重要的作用。然而，目前尚不清楚正常的VSMC是如何维持分化状态的。大电导钙激活钾通道(BKCa)广泛表达于VSMC，调节血管张力。然而，对于BKCa通道在VSMC表型调控中的作用还知之甚少。我们评估了BKCa通道在正常和球囊损伤模型大鼠颈动脉损伤中的表达水平。颈动脉损伤后BKCa-β-1的表达显著降低，并伴有收缩标记物的平行下降。随着传代次数的增加和血小板衍生生长因子-BB的刺激，BKCa-β-1在原代培养的大鼠血管内皮细胞中呈下降趋势。反之，转化生长因子β上调BKCa-β1，同时BKCa-β1水平与VSMC收缩蛋白水平呈正相关。静脉注射血小板衍生生长因子BB可下调颈动脉BKCa-β1的表达。BKCa-β1基因敲除有利于血管平滑肌细胞去分化，表现为细胞形态改变，肌动蛋白纤维结构异常，收缩蛋白表达减少，收缩能力下降。此外，由此产生的VSMC去分化表型增加了增殖、迁移、炎症因子水平和基质金属蛋白酶活性。使用原代培养的人主动脉VSMCs的研究概括了主要发现。人动脉粥样硬化血管中BKCa-β1的蛋白水平降低。BKCa-β1在维持VSMC的收缩表型中起重要作用。BKca-β1作为一种新型的内源性防御剂，可阻止病理性血管平滑肌细胞表型转换，有望成为治疗血管损伤后再狭窄和动脉粥样硬化等疾病的潜在靶点。
Vascular smooth muscle cells (VSMCs) phenotype switching is very important during the pathogenesis and progression of vascular diseases. However, it is not well understood how normal VSMCs maintain the differentiated state. The large-conductance Ca2+-activated K+ (BKCa) channels are widely expressed in VSMCs and regulate vascular tone. Nevertheless, there is limited understanding of the role of the BKCa channel in modulation of the VSMC phenotype. We assessed BKCa channel expression levels in normal and injured carotid arteries from rats of the balloon-injury model. A strong decrease of BKCa-β1 was seen in the injured carotid arteries, accompanied by a parallel decrease of the VSMC contractile markers. BKCa-β1 in primary rat aortic VSMCs was decreased with the increase of passage numbers and the stimulation of platelet-derived growth factor (PDGF)-BB. Conversely, transforming growth factor β upregulated BKCa-β1. Meanwhile, the BKCa-β1 level was positively associated with the levels of VSMC contractile proteins. Intravenous injection of PDGF-BB induced downregulation of BKCa-β1 expression in the carotid arteries. Knockdown of BKCa-β1 favored VSMC dedifferentiation, characterized by altered morphology, abnormal actin fiber organization, decreased contractile proteins expression and reduced contractile ability. Furthermore, the resultant VSMC dedifferentiated phenotype rendered increased proliferation, migration, enhanced inflammatory factors levels, and matrix metalloproteinases activity. Studies using primary cultured aortic VSMCs from human recapitulated key findings. Finally, protein level of BKCa-β1 was reduced in human atherosclerotic arteries. BKCa-β1 is important in the maintenance of the contractile phenotype of VSMCs. As a novel endogenous defender that prevents pathological VSMC phenotype switching, BKCa-β1 may serve as a potential therapeutic target for treating vascular diseases including post-injury restenosis and atherosclerosis.
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影响因子：
10.8
作者：
Cheong A;Li J;Sukumar P;Kumar B;Zeng F;Riches K;Munsch C;Wood IC;Porter KE;Beech DJ
通讯作者：
Beech DJ
影响因子：
15.9
作者：
Amberg, GC;Bonev, AD;Santana, LF
通讯作者：
Santana, LF
影响因子：
64.5
作者：
BATTEGAY, EJ;RAINES, EW;ROSS, R
通讯作者：
ROSS, R
影响因子：
5.6
作者：
BLANK, RS;OWENS, GK
通讯作者：
OWENS, GK
DOI：
10.1085/jgp.116.3.411
发表时间：
2000-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Cox DH;Aldrich RW
通讯作者：
Aldrich RW