Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

in Reproduction
Authors:
Sarah J Delforce School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia
Priority Research Centre for Reproductive Sciences, University of Newcastle, Newcastle, New South Wales, Australia
Hunter Medical Research Institute, Newcastle, New South Wales, Australia

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Eugenie R Lumbers School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia
Priority Research Centre for Reproductive Sciences, University of Newcastle, Newcastle, New South Wales, Australia
Hunter Medical Research Institute, Newcastle, New South Wales, Australia

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Stacey J Ellery The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia

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Padma Murthi Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women’s Hospital, Parkville, Victoria, Australia
Department of Obstetrics & Gynaecology, University of Melbourne, Parkville, Victoria, Australia
The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia

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Kirsty G Pringle School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia
Priority Research Centre for Reproductive Sciences, University of Newcastle, Newcastle, New South Wales, Australia
Hunter Medical Research Institute, Newcastle, New South Wales, Australia

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Correspondence should be addressed to K G Pringle; Email: kirsty.pringle@newcastle.edu.au
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Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

 

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