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Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether <jats:italic>N<\/jats:italic>\u2010acetylcysteine (NAC) and hydrogen sulphide (H<jats:sub>2<\/jats:sub>S) protect cardiovascular function in growth\u2010restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near\u2010term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H<jats:sub>2<\/jats:sub>S gene CTH (i.e. cystathionine \u03b3\u2010lyase) (via quantitative PCR), the production of H<jats:sub>2<\/jats:sub>S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic\/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H<jats:sub>2<\/jats:sub>S production and enhanced third\u2010order femoral artery dilator responses to the H<jats:sub>2<\/jats:sub>S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third\u2010to\u2010fourth order chorionic arteries from FGR pregnancies and in third\u2010order femoral arteries from hypoxic chicken embryos. This NAC\u2010induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3\u00a0methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H<jats:sub>2<\/jats:sub>S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16190-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We investigated the effects between <jats:italic>N<\/jats:italic>\u2010acetylcysteine (NAC) and hydrogen sulphide (H<jats:sub>2<\/jats:sub>S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H<jats:sub>2<\/jats:sub>S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Therefore, the NAC\/H<jats:sub>2<\/jats:sub>S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286266","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T17:44:38Z","timestamp":1720633478000},"page":"3833-3852","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Epigenetic regulation by hypoxia, <i>N<\/i>\u2010acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos"],"prefix":"10.1113","volume":"602","author":[{"given":"Bernardo J.","family":"Krause","sequence":"first","affiliation":[{"name":"Instituto de Ciencias de la Salud Universidad O'Higgins  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4611-2748","authenticated-orcid":false,"given":"Adolfo A.","family":"Paz","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias de la Salud Universidad O'Higgins  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa A. 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