Stimulation of vascular smooth muscle cell proliferation by stiff matrix via the IKCa channel‐dependent Ca2+ signaling. Issue 10 (1st March 2021)

• Record Type: Journal Article
• Authors: Jia, Xiaoling; Yang, Qingmao; Gao, Chao; Chen, Xinlan; Li, Yanan; Su, Hao; Zheng, Yufan; Zhang, Shuwen; Wang, Ziyu; Wang, Haikun; Jiang, Lin‐Hua; Sun, Yan; Fan, Yubo
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 10(2021)
• Page Start: 6897
• Page End: 6906
• Publication Date: 2021-03-01
• Subjects: Ca2+ -- extracellular signal‐regulated kinases -- intermediate‐conductance Ca2+‐activated K+ channel -- matrix stiffness -- vascular smooth muscle cell proliferation; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30349
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: 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 Ca 2+ ‐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 IKCa channel. Stiff substrate‐induced cell proliferation was suppressed by pharmacological inhibition using TRAM34, an IKCa channel blocker, or genetic depletion of the IKCa channel. In addition, stiff substrate‐induced cell proliferation was also suppressed by reducing extracellular Ca 2+ concentration using EGTA or intracellular Ca 2+ 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 IKCa channel expression to enhance intracellular Ca 2+ 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. Abstract : The substrates with pathologically relevant stiffness upregulate the intermediate‐conductance Ca 2+ ‐activated K + (IKCa ) channel expression to enhance intracellular Ca 2+ signaling and subsequent activation of the signal‐regulated kinase (ERK) signal pathway to drive cell proliferation. These findings provide a novel mechanism by which vascular stiffening regulates vascular smooth muscle cell (VSMC) function.