{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:06:21Z","timestamp":1779793581394,"version":"3.53.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Pregestational diabetes (PGD) increases congenital heart defect (CHD) risk over 5\u2010fold. Maternal exercise enhances eNOS (endothelial nitric oxide synthase) activity, benefiting embryos, though its causal role remains unclear. This study investigated the role of eNOS in maternal exercise\u2010mediated protection of fetal heart development in a PGD mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      PGD was induced in eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      or wild\u2010type female mice via streptozotocin before breeding with wild\u2010type or eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      males. Pregnant females had access to a running wheel for voluntary exercise or remained sedentary. Fetuses were collected at embryonic day 18.5 for genotyping and CHD assessment. Embryonic day 12.5 hearts were analyzed for proliferation, apoptosis, oxidative stress, and eNOS protein levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Maternal exercise normalized litter size and mortality rates in offspring of diabetic eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      females but did not reduce CHD incidence in offspring of wild\u2010type or eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      females with PGD. CHDs included septal defects, double outlet right ventricle, and valve defects. Exercise increased coronary artery density but not capillary density. Proliferation deficits at embryonic day 12.5 were restored by exercise, yet oxidative stress remained elevated. Maternal exercise in eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      dams during PGD did not significantly change eNOS protein or phosphorylation levels in both eNOS\n                      <jats:sup>+\/+<\/jats:sup>\n                      and eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      fetal hearts. Offspring genotype did not affect CHD incidence, cell proliferation, apoptosis, or 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\">\n                      Maternal exercise does not prevent CHDs in PGD offspring of eNOS\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mice. Its ability to mitigate PGD\u2010induced oxidative stress is eNOS dependent and essential for improving heart morphology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.042848","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T10:24:36Z","timestamp":1767090276000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Haploinsufficiency of Endothelial Nitric Oxide Synthase Mitigates Beneficial Effects of Maternal Exercise on Fetal Heart Development During Pregestational Diabetes"],"prefix":"10.1161","volume":"15","author":[{"given":"Ryleigh","family":"Van Neck","sequence":"first","affiliation":[{"name":"Schulich School of Medicine and Dentistry","place":["London, Canada"]},{"name":"Western University","place":["London, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangru","family":"Lu","sequence":"additional","affiliation":[{"name":"Schulich School of Medicine and Dentistry","place":["London, Canada"]},{"name":"Western University","place":["London, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3872-7897","authenticated-orcid":false,"given":"Thomas","family":"Pan","sequence":"additional","affiliation":[{"name":"Schulich School of Medicine and Dentistry","place":["London, Canada"]},{"name":"Western University","place":["London, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Du","sequence":"additional","affiliation":[{"name":"Schulich School of Medicine and Dentistry","place":["London, Canada"]},{"name":"Western University","place":["London, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9799-7976","authenticated-orcid":false,"given":"Lambertus J.","family":"Wisse","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["Leiden, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0528-7464","authenticated-orcid":false,"given":"Marco C.","family":"DeRuiter","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["Leiden, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9739-2765","authenticated-orcid":false,"given":"Qingping","family":"Feng","sequence":"additional","affiliation":[{"name":"Schulich School of Medicine and Dentistry","place":["London, Canada"]},{"name":"Western University","place":["London, Canada"]},{"name":"Schulich School of Medicine and Dentistry","place":["London, Canada"]},{"name":"Western University","place":["London, Canada"]},{"name":"London Health Sciences Centre Research Institute","place":["London, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11092381"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.21037\/tp-21-297"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017465"},{"key":"e_1_3_2_5_2","unstructured":"International Diabetes Federation . Diabetes Facts & figures [Internet]. 2024 Accessed Jun 10 2024. https:\/\/idf.org\/about\u2010diabetes\/diabetes\u2010facts\u2010figures\/."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyz009"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/bdr2.1435"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2840-13-46"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20457"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.115.001138"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14439"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000024114.82981.EA"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.168567"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4065\/71.4.346"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.37.22810"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2012.04.004"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.034637"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.044990"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.20.2345"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.953912"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs306"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0190"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.009624"},{"key":"e_1_3_2_24_2","unstructured":"International Diabetes Foundation . IDF Diabetes Atlas 2021 | IDF Diabetes Atlas [Internet]. 2021 Accessed Dec 5 2024. https:\/\/diabetesatlas.org\/atlas\/tenth\u2010edition\/."},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2003.05.003"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605137114"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/1747-1028-1-32"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.121308"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.23.2839"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9926(199712)56:6<343::AID-TERA1>3.0.CO;2-X"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/7404082"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/1679045"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1089\/152308601300185179"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.95085"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/3846122"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12212544"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(05)96027-8"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9551"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.03.004"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8100436"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.187559"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.09.004"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.125.042848","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T10:51:46Z","timestamp":1779792706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.125.042848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,6]]}},"alternative-id":["10.1161\/JAHA.125.042848"],"URL":"https:\/\/doi.org\/10.1161\/jaha.125.042848","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]},"assertion":[{"value":"2025-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e042848"}}