Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.

Autor: Krause BJ; Instituto de Ciencias de la Salud, Universidad O'Higgins, Santiago, Chile., Paz AA; Instituto de Ciencias de la Salud, Universidad O'Higgins, Santiago, Chile., Garrud TAC; Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge, UK., Peñaloza E; Instituto de Ciencias de la Salud, Universidad O'Higgins, Santiago, Chile., Vega-Tapia F; Instituto de Ciencias de la Salud, Universidad O'Higgins, Santiago, Chile., Ford SG; Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge, UK., Niu Y; Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge, UK.; Centre for Trophoblast Research, University of Cambridge, Cambridge, UK., Giussani DA; Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge, UK.; Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.; BHF Cardiovascular Centre for Research Excellence, University of Cambridge, Cambridge, UK.; Strategic Research Initiative in Reproduction, University of Cambridge, Cambridge, UK.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2024 Aug; Vol. 602 (15), pp. 3833-3852. Date of Electronic Publication: 2024 Jul 10.
DOI: 10.1113/JP286266
Abstrakt: Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. 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 N-acetylcysteine (NAC) and hydrogen sulphide (H 2 S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H 2 S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H 2 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 2 S production and enhanced third-order femoral artery dilator responses to the H 2 S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced 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 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H 2 S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: 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. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H 2 S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H 2 S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H 2 S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.
(© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
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