{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:11:30Z","timestamp":1788361890561,"version":"build-2803163510"},"reference-count":67,"publisher":"SAGE Publications","issue":"21-22","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"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":[[2020,11]]},"abstract":"\n Severe fetal growth restriction (FGR) affects 1:500 pregnancies, is untreatable and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) and lack of bioavailable VEGF due to placental insufficiency is a major cause. Transduction of uterine arteries in normal or FGR sheep and guinea pigs using an adenovirus (Ad) encoding\n VEGF<\/jats:italic>\n isoforms A (Ad.VEGF-A\n 165<\/jats:sub>\n ) and a FLAG-tagged pre-processed short form D (D\n \u0394N\u0394C<\/jats:sup>\n , Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n -FLAG) increases endothelial nitric oxide expression, enhances relaxation and reduces constriction of the uterine arteries and their branches. UBF and angiogenesis are increased long term, improving fetal growth\n in utero<\/jats:italic>\n . For clinical trial development we compared\n Ad.VEGF<\/jats:uri>\n vector transduction efficiency and function in endothelial cells (ECs) derived from different species. We aimed to compare the transduction efficiency and function of the pre-clinical study Ad. constructs (Ad.VEGF-A\n 165<\/jats:sub>\n , Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n -FLAG) with the intended clinical trial construct (Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n ) where the FLAG tag is removed. We infected ECs from human umbilical vein, pregnant sheep uterine artery, pregnant guinea pig aorta and non-pregnant rabbit aorta, with increasing multiplicity of infection (MOI) for 24 or 48 hours of three\n Ad.VEGF<\/jats:uri>\n vectors, compared to control Ad. containing the\n LacZ<\/jats:italic>\n gene (\n Ad.LacZ<\/jats:uri>\n ). VEGF supernatant expression was analysed by ELISA. Functional assessment used tube formation assay and Erk-Akt phosphorylation by ELISA. VEGF expression was higher after Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n -FLAG and Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n transduction compared to Ad.VEGF-A\n 165<\/jats:sub>\n in all EC types (*\n p<\/jats:italic>\n \u2009<\u20090.001). Tube formation was higher in ECs transduced with Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n in all species compared to other constructs (***\n p<\/jats:italic>\n \u2009<\u20090.001, *\n p<\/jats:italic>\n \u2009<\u20090.05 with rabbit aortic ECs). Phospho-Erk and phospho-Akt assays displayed no differences between the three vector constructs, whose effect was, as in other experiments, higher than\n Ad.LacZ<\/jats:uri>\n (***\n p<\/jats:italic>\n \u2009<\u20090.001). In conclusion, we observed high transduction efficiency and functional effects of Ad.VEGF-D\n \u0394N\u0394C<\/jats:sup>\n vector with comparability in major pathway activation to constructs used in pre-clinical studies, supporting its use in a clinical trial.\n <\/jats:p>","DOI":"10.1089\/hum.2020.006","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T03:07:16Z","timestamp":1601348836000},"page":"1190-1202","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Comparison of Efficiency and Function of Vascular Endothelial Growth Factor Adenovirus Vectors in Endothelial Cells for Gene Therapy of Placental Insufficiency"],"prefix":"10.1177","volume":"31","author":[{"given":"Carlo","family":"Rossi","sequence":"first","affiliation":[{"name":"Elizabeth Garrett Anderson Institute for Women's Health"},{"name":"Centre for Cardiovascular Biology and Medicine; University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Lees","sequence":"additional","affiliation":[{"name":"Elizabeth Garrett Anderson Institute for Women's Health"},{"name":"Centre for Cardiovascular Biology and Medicine; University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vedanta","family":"Mehta","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Biology and Medicine; University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommi","family":"Heikura","sequence":"additional","affiliation":[{"name":"A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Martin","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Biology and Medicine; University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Zachary","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Biology and Medicine; University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Spencer","sequence":"additional","affiliation":[{"name":"Elizabeth Garrett Anderson Institute for Women's Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"Peebles","sequence":"additional","affiliation":[{"name":"Elizabeth Garrett Anderson Institute for Women's Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Shaw","sequence":"additional","affiliation":[{"name":"FinVector Oy, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Karhinen","sequence":"additional","affiliation":[{"name":"FinVector Oy, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Yla-Herttuala","sequence":"additional","affiliation":[{"name":"A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"},{"name":"Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"David","sequence":"additional","affiliation":[{"name":"Elizabeth Garrett Anderson Institute for Women's Health"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,11,13]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01892"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-0528.2003.t01-1-02163.x"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f108"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/pd.4401"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2017.11.565"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000003070"},{"key":"e_1_3_5_8_2","unstructured":"Royal College of Obstetricians and Gynaecologists. 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