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The intermediate conductance calcium\u2010activated potassium (IK<jats:sub>Ca<\/jats:sub>) channel plays a critical role in VSMC proliferation by raising the intracellular calcium concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>), but the underlying mechanism is still not unclear. Here we investigated the cooperation between IK<jats:sub>Ca<\/jats:sub> and transient receptor potential canonical 1 (TRPC1) channels in mediating extracellular Ca<jats:sup>2+<\/jats:sup> entry, which in turn activates downstream Ca<jats:sup>2+<\/jats:sup> signalling in the regulation of VSMC proliferation using serum\u2010induced cell proliferation model. Serum\u2010induced cell proliferation was accompanied with up\u2010regulation of IK<jats:sub>Ca<\/jats:sub> expression and an increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. Serum\u2010induced cell proliferation and increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> were suppressed by IK<jats:sub>Ca<\/jats:sub> inhibition with TRAM\u201034 or IK<jats:sub>Ca<\/jats:sub> knockdown. Serum\u2010induced cell proliferation was strongly reduced by the removal of extracellular Ca<jats:sup>2+<\/jats:sup> with EGTA or intracellular Ca<jats:sup>2+<\/jats:sup> with BAPTA\u2010AM and, additionally, by TRPC1 knockdown. Moreover, the increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> induced by serum or by IK<jats:sub>Ca<\/jats:sub> activation with 1\u2010EBIO was attenuated by TRPC1 knockdown. Finally, serum induced ERK1\/2 activation, which was attenuated by treatment with TRAM\u201034 or BAPTA\u2010AM, as well as TRPC1 knockdown. Consistently, serum\u2010induced cell proliferation was suppressed by ERK1\/2 inhibition with PD98059. Taken together, these results suggest that the IK<jats:sub>Ca<\/jats:sub> and TRPC1 channels cooperate in mediating Ca<jats:sup>2+<\/jats:sup> influx that activates the ERK1\/2 pathway to promote cell proliferation, thus providing new mechanistic insights into VSMC proliferation.<\/jats:p>","DOI":"10.1111\/cpr.13385","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T09:43:14Z","timestamp":1671788594000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Functional cooperation between <scp>IK<sub>Ca<\/sub><\/scp> and <scp>TRPC1<\/scp> channels regulates serum\u2010induced vascular smooth muscle cell proliferation via mediating Ca<sup>2+<\/sup> influx and <scp>ERK1<\/scp>\/2 activation"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5806-7273","authenticated-orcid":false,"given":"Xiaoling","family":"Jia","sequence":"first","affiliation":[{"name":"Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, and with the School of Engineering Medicine Beihang University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, and with the School of Engineering Medicine Beihang University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, and with the School of Engineering Medicine Beihang University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haikun","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, and with the School of Engineering Medicine Beihang University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengxi","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, and with the School of Engineering Medicine Beihang University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-0411","authenticated-orcid":false,"given":"Lin\u2010Hua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Sino\u2010UK Joint Laboratory of Brain Function and Injury of Henan Province, and Department of Physiology and Pathophysiology Xinxiang Medical University  Xinxiang China"},{"name":"A4245\u2010Transplantation, Immunology and Inflammation, Faculty of Medicine University of Tours  Tours France"},{"name":"School of Biomedical Sciences, Faculty of Biological Sciences University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Fan","sequence":"additional","affiliation":[{"name":"Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, and with the School of Engineering Medicine Beihang University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.08.019"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0402-403"},{"issue":"2","key":"e_1_2_9_4_1","first-page":"119","article-title":"An overview of potential molecular mechanisms involved in VSMC phenotypic modulation","volume":"154","author":"Hang MJ","year":"2016","journal-title":"Histochem Cell Biol"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03085963"},{"issue":"5694","key":"e_1_2_9_6_1","first-page":"1","article-title":"The role of vascular smooth muscle 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