{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:00:51Z","timestamp":1790485251047,"version":"4.1.0"},"reference-count":42,"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":[[2016,4,3]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Congenital heart disease is the most common type of birth defect, affecting \u22482% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for &gt;50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">NOTCH<\/jats:styled-content>\n                        1\n                      <\/jats:italic>\n                      were a cause of bicuspid aortic valve in nonsyndromic autosomal\u2010dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in\n                      <jats:italic>Notch1<\/jats:italic>\n                      \u2010haploinsufficient adult mice backcrossed into a\n                      <jats:italic>Nos3<\/jats:italic>\n                      \u2010null background.\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                      Here, we described the congenital cardiac abnormalities in\n                      <jats:italic>Notch1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>;Nos3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      embryos that led to \u224865% lethality by postnatal day 10. Although expected Mendelian ratios of\n                      <jats:italic>Notch1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>;Nos3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of\n                      <jats:italic>Notch1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>;Nos3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for\n                      <jats:italic>Notch1<\/jats:italic>\n                      specifically in endothelial and endothelial\u2010derived cells in a\n                      <jats:italic>Nos3<\/jats:italic>\n                      \u2010null background and found that\n                      <jats:italic>Notch1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl<\/jats:italic>\n                        \/+\n                      <\/jats:sup>\n                      ;\n                      <jats:italic>Tie2\u2010Cre<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      <jats:italic>;Nos3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice recapitulate the congenital cardiac phenotype of\n                      <jats:italic>Notch1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>;Nos3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      embryos.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.<\/jats:p>\n                  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