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In this study, we investigated changes in the vascular endothelium in mice in which Cant\u00fa syndrome\u2013associated\n                    <jats:italic>Kcnj8<\/jats:italic>\n                    or\n                    <jats:italic>Abcc9<\/jats:italic>\n                    mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cant\u00fa mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either K\n                    <jats:sub>ATP<\/jats:sub>\n                    GOF or acute activation of K\n                    <jats:sub>ATP<\/jats:sub>\n                    channels with pinacidil increased the amplitude and frequency of wave-like Ca\n                    <jats:sup>2+<\/jats:sup>\n                    events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling activity in arterial endothelial cells from Cant\u00fa mice was associated with elevated mitochondrial [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with K\n                    <jats:sub>ATP<\/jats:sub>\n                    GOF mutations. We conclude that mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cant\u00fa syndrome.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.176212","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T12:02:00Z","timestamp":1722513720000},"source":"Crossref","is-referenced-by-count":14,"title":["Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cant\u00fa syndrome"],"prefix":"10.1172","volume":"9","author":[{"given":"Elsayed","family":"Metwally","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, Nevada, USA."},{"name":"Department of Cytology and 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