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Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs .<\/jats:p>","DOI":"10.1093\/function\/zqae027","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:46:55Z","timestamp":1716943615000},"source":"Crossref","is-referenced-by-count":2,"title":["Electrophysiology of Human iPSC-derived Vascular Smooth Muscle Cells and Cell-autonomous Consequences of Cant\u00fa Syndrome Mutations"],"prefix":"10.1152","volume":"5","author":[{"given":"Alex","family":"Hanson","sequence":"first","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine , St. Louis, MO 63110 , USA"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine , St. Louis, MO 63110 , 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R","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Washington University in Saint Louis , St. Louis, MO 63110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4929-2134","authenticated-orcid":false,"given":"Colin G","family":"Nichols","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine , St. Louis, MO 63110 , USA"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine , St. Louis, MO 63110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"issue":"8","key":"2024091011562862300_bib1","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/ncb3205","article-title":"Generation of vascular endothelial and smooth muscle cells from human pluripotent stem 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