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Circulating aldosterone levels increase in patients with diabetes. Aldosterone can directly affect vascular function via activation of the mineralocorticoid receptor (MR). We hypothesized that aldosterone via endothelial MR impairs endothelial function in a murine model of experimental diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Endothelial cell\u2010specific mineralocorticoid receptor knockout MR<jats:sup>flox\/flox<\/jats:sup>; Tie2\u2010Cre mice (ECMR\u2010KO) and wild\u2010type FVB littermates were subjected to an experimental type\u20101 diabetic model by low dose streptozotocin injections (55mg\/kg\/day) for five consecutive days. After 10\u00a0weeks of diabetes, second\u2010order mesenteric resistance arteries were perfused ex vivo to evaluate vessel contractility and endothelial function. The effect of ex vivo incubation with aldosterone with and without the antagonist, spironolactone was determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Diabetic ECMR\u2010KO and wild\u2010type mice had similar, elevated, plasma aldosterone concentration while only diabetic wild\u2010type mice displayed elevated urine albumin excretion and cardiac and kidney hypertrophy at 10\u00a0weeks. There were no differences in contraction (Emax and EC<jats:sub>50<\/jats:sub>) to thromboxane receptor agonist (U46619) and elevated K<jats:sup>+<\/jats:sup> between groups. Wild\u2010type diabetic mice showed impaired acetylcholine (ACh)\u2010dependent relaxation, while diabetic ECMR\u2010KO mice had intact ACh\u2010mediated relaxation. Aldosterone incubation ex vivo impaired ACh mediated relaxation and rendered responses similar to diabetic WT arteries. Direct, ex vivo aldosterone effects were absent in ECMR\u2010KO animals. Ex vivo inhibitory effects of aldosterone on endothelial relaxation in arteries from WT were abolished by spironolactone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings show that endothelial cell mineralocorticoid receptor activation accounts for diabetes\u2010induced systemic endothelial dysfunction in experimental diabetes and may explain the cardiovascular protection by MR antagonists in diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13731","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T08:02:17Z","timestamp":1631606537000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Endothelial mineralocorticoid receptor ablation confers protection towards endothelial dysfunction in experimental diabetes in mice"],"prefix":"10.1111","volume":"234","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3250-4049","authenticated-orcid":false,"given":"Kristina S.","family":"Lyngs\u00f8","sequence":"first","affiliation":[{"name":"Department of Cardiovascular and Renal Research Institute of Molecular Medicine University of Southern Denmark Odense C Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7607-213X","authenticated-orcid":false,"given":"Boye L.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Research Institute of Molecular Medicine University of Southern Denmark Odense C Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pernille B. 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