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dc.contributor.authorItani, Nozomien
dc.contributor.authorSkeffington, Katie Len
dc.contributor.authorBeck, Christianen
dc.contributor.authorGiussani, Dinoen
dc.date.accessioned2017-02-06T10:06:37Z
dc.date.available2017-02-06T10:06:37Z
dc.date.issued2017-03en
dc.identifier.issn0022-3751
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262306
dc.description.abstractThere is a need for developing clinically translatable therapy for preventing fetal origins of cardiovascular disease in pregnancy complicated by chronic fetal hypoxia. Evidence shows that sildenafil protects placental perfusion and fetal growth. However, whether beneficial effects of sildenafil transcend onto the fetal heart and circulation in complicated development is unknown. We isolated the direct effects of sildenafil on the fetus using the chick embryo and hypothesised that sildenafil also protects fetal cardiovascular function in hypoxic development. Chick embryos ($\textit{n}$ = 11 per group) were incubated in normoxia or hypoxia (14% O$_{2}$) from day 1 and treated with sildenafil (4 mg kg$^{-1}$ day$^{-1}$) from day 13 of the 21-day incubation. Hypoxic incubation increased oxidative stress (4-hydroxynonenal, 141.1 ± 17.6% of normoxic control), reduced superoxide dismutase (60.7 ± 6.3%), increased phosphodiesterase type 5 expression (167 ± 13.7%) and decreased nitric oxide bioavailability (54.7 ± 6.1%) in the fetal heart, and promoted peripheral endothelial dysfunction (70.9 ± 5.6% AUC of normoxic control; all $\textit{P}$ < 0.05). Sildenafil treatment after onset of chronic hypoxia prevented the increase in phosphodiesterase expression (72.5 ± 22.4%), protected against oxidative stress (94.7 ± 6.2%) and normalised nitric oxide bioavailability (115.6 ± 22.3%) in the fetal heart, and restored endothelial function in the peripheral circulation (89.8 ± 2.9%). Sildenafil protects the fetal heart and circulation directly in hypoxic development via mechanisms including decreased oxidative stress and enhanced nitric oxide bioavailability. Sildenafil may be a good translational candidate for human antioxidant therapy to prevent fetal origins of cardiovascular dysfunction in adverse pregnancy.
dc.description.sponsorshipBritish Heart Foundation.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.language.isoenen
dc.publisherWiley
dc.titleSildenafil therapy for fetal cardiovascular dysfunction during hypoxic development: studies in the chick embryo.en
dc.typeArticle
prism.endingPage1573
prism.publicationDate2017en
prism.publicationNameThe Journal of physiologyen
prism.startingPage1563
prism.volume595en
dc.identifier.doi10.17863/CAM.7561
dcterms.dateAccepted2016-11-07en
rioxxterms.versionofrecord10.1113/jp273393en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-03en
dc.contributor.orcidGiussani, Dino [0000-0002-1308-1204]
dc.identifier.eissn1469-7793
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (BB/E002668/1)
pubs.funder-project-idBritish Heart Foundation (RG/06/006/22028)
pubs.funder-project-idBritish Heart Foundation (PG/10/99/28656)
pubs.funder-project-idBritish Heart Foundation (RG/11/16/29260)
pubs.funder-project-idBritish Heart Foundation (FS/12/74/29778)
pubs.funder-project-idBritish Heart Foundation (PG/14/5/30547)
rioxxterms.freetoread.startdate2017-11-12


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