{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:22:13Z","timestamp":1788916933585,"version":"build-2803163510"},"reference-count":40,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2014,3,4]],"date-time":"2014-03-04T00:00:00Z","timestamp":1393891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2014,3,4]],"date-time":"2014-03-04T00:00:00Z","timestamp":1393891200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:p>\n                    Fetal growth restriction (FGR) occurs in \u223c8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestation correlates with reduced lamb birthweight near term. Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently offered a high intake (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =45) or control intake (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =12) of a complete diet to generate FGR or normal fetoplacental growth, respectively. High-intake ewes were randomized midgestation to receive bilateral UtA injections of 5\u00d710\n                    <jats:sup>11<\/jats:sup>\n                    particles Ad.VEGF-A\n                    <jats:sub>165<\/jats:sub>\n                    (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =18), control vector Ad.LacZ (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =14), or control saline (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =13). Fetal growth\/well-being were evaluated using serial ultrasound. UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularization within the perivascular adventitia, and placental mRNA expression of angiogenic factors\/receptors were examined using organ bath analysis, anti-vWF immunohistochemistry, and qRT-PCR, respectively. Ad.VEGF significantly increased ultrasonographic fetal growth velocity at 3\u20134 weeks postinjection (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    =0.016\u20130.047). At 0.9 gestation fewer fetuses were markedly growth-restricted (birthweight &gt;2SD below contemporaneous control-intake mean) after Ad.VEGF therapy. There was also evidence of mitigated fetal brain sparing (lower biparietal diameter-to-abdominal circumference and brain-to-liver weight ratios). No effects were observed on UBF or neovascularization; however, Ad.VEGF-transduced vessels demonstrated strikingly enhanced vasorelaxation. Placental efficiency (fetal-to-placental weight ratio) and\n                    <jats:italic toggle=\"yes\">FLT1\/KDR<\/jats:italic>\n                    mRNA expression were increased in the maternal but not fetal placental compartments, suggesting downstream effects on placental function. Ad.VEGF gene therapy improves fetal growth in a sheep model of FGR, although the precise mechanism of action remains unclear.\n                  <\/jats:p>","DOI":"10.1089\/hum.2013.214","type":"journal-article","created":{"date-parts":[[2014,3,4]],"date-time":"2014-03-04T14:36:40Z","timestamp":1393943800000},"page":"375-384","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":80,"title":["Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies"],"prefix":"10.1177","volume":"25","author":[{"given":"David J.","family":"Carr","sequence":"first","affiliation":[{"name":"University College London","place":["United Kingdom"]},{"name":"University of Aberdeen","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Wallace","sequence":"additional","affiliation":[{"name":"University of Aberdeen","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond P.","family":"Aitken","sequence":"additional","affiliation":[{"name":"University of Aberdeen","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Milne","sequence":"additional","affiliation":[{"name":"University of Aberdeen","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vedanta","family":"Mehta","sequence":"additional","affiliation":[{"name":"University College London","place":["United Kingdom"]},{"name":"University College London","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Martin","sequence":"additional","affiliation":[{"name":"University College London","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian C.","family":"Zachary","sequence":"additional","affiliation":[{"name":"University College London","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"Peebles","sequence":"additional","affiliation":[{"name":"University College London","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"David","sequence":"additional","affiliation":[{"name":"University College London","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2014,3,4]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003081-200606000-00009"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(00)70513-8"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ultrasmedbio.2011.06.016"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2012.05.008"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.106.4.659"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2009.06.006"},{"key":"e_1_3_3_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2008.102"},{"key":"e_1_3_3_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006254-200103000-00023"},{"key":"e_1_3_3_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.9041"},{"key":"e_1_3_3_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003081-200606000-00012"},{"key":"e_1_3_3_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006254-199606000-00023"},{"key":"e_1_3_3_13_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-0528.2003.02014.x"},{"key":"e_1_3_3_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2009.06.005"},{"key":"e_1_3_3_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2005-6-2-209"},{"key":"e_1_3_3_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-0528.2003.t01-1-02163.x"},{"key":"e_1_3_3_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(03)00173-8"},{"key":"e_1_3_3_18_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-06-0294"},{"key":"e_1_3_3_19_1","doi-asserted-by":"publisher","DOI":"10.1515\/JPM.2008.050"},{"key":"e_1_3_3_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041367"},{"key":"e_1_3_3_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.158"},{"key":"e_1_3_3_22_1","first-page":"241","volume-title":"Handbook of Physiology","author":"Meschia G.","year":"1983","unstructured":"Meschia G. (1983). Circulation to female reproductive organs. In Handbook of Physiology, Sect. 2, Vol. III, Part 1. Shepherd J.T., and Abboud F.M., eds. (American Physiological Society, Bethesda, MD) pp 241\u2013269."},{"key":"e_1_3_3_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2008.08.029"},{"key":"e_1_3_3_24_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2005-1286"},{"key":"e_1_3_3_25_1","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2003.155"},{"key":"e_1_3_3_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2004.03.008"},{"key":"e_1_3_3_27_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.104.037234"},{"key":"e_1_3_3_28_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-08-0516"},{"key":"e_1_3_3_29_1","doi-asserted-by":"publisher","DOI":"10.2527\/1995.7361839x"},{"key":"e_1_3_3_30_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0021859600063309"},{"key":"e_1_3_3_31_1","first-page":"379","article-title":"Studies on experimental growth retardation in sheep. 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