Stimulation of vascular smooth muscle cell proliferation by stiff matrix via the IKCa channel-dependent Ca2+ signaling
Stimulation of vascular smooth muscle cell proliferation by stiff matrix via the IKCa channel-dependent Ca2+ signaling
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刚性基质通过 IKCa 通道依赖性 Ca2 信号传导刺激血管平滑肌细胞增殖
DOI：
10.1002/jcp.30349
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发表时间：
2021-03-01
影响因子：
5.6
通讯作者：
Fan，Yubo
中科院分区：
文献类型：
--
作者：
Jia，Xiaoling;Yang，Qingmao;Fan，Yubo
血管硬化是心血管疾病 (CVD) 的早期常见特征，它会刺激血管平滑肌细胞 (VSMC) 增殖，从而反过来加速 CVD 的进展。然而，细胞外基质硬度伴随血管硬化调节 VSMC 增殖的机制仍然很大程度上未知。在本研究中，我们通过在柔软和坚硬的聚二甲基硅氧烷基底上生长 A7r5 细胞，研究了中间电导 Ca2+ 激活的 K+（IKCa）通道在 VSMC 增殖的基质硬度调节中的作用，这些基底的硬度分别接近生理和病理条件下的动脉硬度。硬基质刺激细胞增殖并上调 IKCa 通道的表达。使用 IKCa 通道阻滞剂 TRAM34 的药理抑制或 IKCa 通道的遗传耗竭可抑制硬基质诱导的细胞增殖。此外，通过使用 EGTA 降低细胞外 Ca2+ 浓度或使用 BAPTA-AM 降低细胞内 Ca2+ 浓度，也可以抑制硬基质诱导的细胞增殖。此外，硬基质诱导细胞外信号调节激酶（ERK）的激活，而 TRAM34 或 BAPTA-AM 处理可抑制这种激活。用 ERK 抑制剂 PD98059 处理可抑制硬基质诱导的细胞增殖。综上所述，这些结果表明，具有病理相关硬度的基质上调 IKCa 通道表达，增强细胞内 Ca2+ 信号传导，并随后激活 ERK 信号通路，从而驱动细胞增殖。这些发现提供了血管硬化调节 VSMC 功能的新机制。
Vascular stiffening, an early and common characteristic of cardiovascular diseases (CVDs), stimulates vascular smooth muscle cell (VSMC) proliferation which reciprocally accelerates the progression of CVDs. However, the mechanisms by which extracellular matrix stiffness accompanying vascular stiffening regulates VSMC proliferation remain largely unknown. In the present study, we examined the role of the intermediate‐conductance Ca2+‐activated K+(IKCa) channel in the matrix stiffness regulation of VSMC proliferation by growing A7r5 cells on soft and stiff polydimethylsiloxane substrates with stiffness close to these of arteries under physiological and pathological conditions, respectively. Stiff substrates stimulated cell proliferation and upregulated the expression of the IKCachannel. Stiff substrate‐induced cell proliferation was suppressed by pharmacological inhibition using TRAM34, an IKCachannel blocker, or genetic depletion of the IKCachannel. In addition, stiff substrate‐induced cell proliferation was also suppressed by reducing extracellular Ca2+concentration using EGTA or intracellular Ca2+concentration using BAPTA‐AM. Moreover, stiff substrate induced activation of extracellular signal‐regulated kinases (ERKs), which was inhibited by treatment with TRAM34 or BAPTA‐AM. Stiff substrate‐induced cell proliferation was suppressed by treatment with PD98059, an ERK inhibitor. Taken together, these results show that substrates with pathologically relevant stiffness upregulate the IKCachannel expression to enhance intracellular Ca2+signaling and subsequent activation of the ERK signal pathway to drive cell proliferation. These findings provide a novel mechanism by which vascular stiffening regulates VSMC function.