{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T14:46:40Z","timestamp":1785768400531,"version":"3.56.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,2,20]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (\n              <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n              ) activation, we tested the hypothesis that\n              <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n              in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Male and female endothelial cell\u2013specific\n              <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n              knockout mice and\n              <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n              \u2010intact littermates were randomized to high\u2010fat\u2010diet\u2013induced obesity or obesity with hyperlipidemia induced by adeno\u2010associated virus\u2013based vector targeting transfer of the mutant stable form (DY mutation) of the human\n              <jats:italic>PCSK9<\/jats:italic>\n              (proprotein convertase subtilisin\/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity\u2010induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium\u2010derived hyperpolarization\u2013mediated relaxation along with increased\n              <jats:styled-content style=\"fixed-case\">SK<\/jats:styled-content>\n              3 expression. Conversely, in females, endothelium\u2010derived hyperpolarization was significantly impaired by obesity with lower\n              <jats:styled-content style=\"fixed-case\">IK<\/jats:styled-content>\n              1 expression and by hyperlipidemia with lower\n              <jats:styled-content style=\"fixed-case\">IK<\/jats:styled-content>\n              1 and\n              <jats:styled-content style=\"fixed-case\">SK<\/jats:styled-content>\n              3 expression, loss of H\n              <jats:sub>2<\/jats:sub>\n              O\n              <jats:sub>2<\/jats:sub>\n              \u2010mediated vasodilation, and increased superoxide production. Endothelial cell\u2013\n              <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n              deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium\u2010derived hyperpolarization in females, endothelial cell\u2013\n              <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n              deletion enhanced nitric oxide and prevented hyperlipidemia\u2010induced oxidative stress.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">These data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.117.007675","type":"journal-article","created":{"date-parts":[[2018,2,17]],"date-time":"2018-02-17T01:10:33Z","timestamp":1518829833000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":78,"title":["Sex\u2010Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors"],"prefix":"10.1161","volume":"7","author":[{"given":"Ana P.","family":"Davel","sequence":"first","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA"},{"name":"Department of Structural and Functional Biology, Institute of Biology, University of Campinas, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lu","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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