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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\u2010conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup>\u00a0(IK<jats:sub>Ca<\/jats:sub>) 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 IK<jats:sub>Ca<\/jats:sub> channel. Stiff substrate\u2010induced cell proliferation was suppressed by pharmacological inhibition using TRAM34, an IK<jats:sub>Ca<\/jats:sub> channel blocker, or genetic depletion of the IK<jats:sub>Ca<\/jats:sub> channel. In addition, stiff substrate\u2010induced cell proliferation was also suppressed by reducing extracellular Ca<jats:sup>2+<\/jats:sup> concentration using EGTA or intracellular Ca<jats:sup>2+<\/jats:sup> concentration using BAPTA\u2010AM. Moreover, stiff substrate induced activation of extracellular signal\u2010regulated kinases (ERKs), which was inhibited by treatment with TRAM34 or BAPTA\u2010AM. Stiff substrate\u2010induced cell proliferation was suppressed by treatment with PD98059, an ERK inhibitor. Taken together, these results show that substrates with pathologically relevant stiffness upregulate the IK<jats:sub>Ca<\/jats:sub> channel expression to enhance intracellular Ca<jats:sup>2+<\/jats:sup> 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.<\/jats:p>","DOI":"10.1002\/jcp.30349","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T07:37:08Z","timestamp":1614670628000},"page":"6897-6906","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Stimulation of vascular smooth muscle cell proliferation by stiff matrix via the IK<sub>Ca<\/sub> channel\u2010dependent Ca<sup>2+<\/sup> signaling"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5806-7273","authenticated-orcid":false,"given":"Xiaoling","family":"Jia","sequence":"first","affiliation":[{"name":"Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering Beihang University  Beijing China"},{"name":"School of 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