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      Dysregulated flow‐mediated vasodilatation in the human placenta in fetal growth restriction

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          Abstract

          Key points

          • A correlation was found between in vivo umbilical artery Doppler velocimetry and resistance to fetal‐side flow in the human ex vivo dually perfused placenta, highlighting that the fetoplacental vascular bed is a key site of resistance to umbilico‐placental flow in pregnancy.

          • We discovered high resistance and poor flow‐mediated vasodilatory responses in placentas from pregnancies associated with fetal growth restriction (FGR).

          • Endothelial cells isolated from the FGR placentas and grown in static and flow culture showed a dysregulated phenotype, with biochemical signalling demonstrating a failed compensatory response to high blood‐flow resistance.

          Abstract

          Increased vascular resistance and reduced fetoplacental blood flow are putative aetiologies in the pathogenesis of fetal growth restriction (FGR); however, the regulating sites and mechanisms remain unclear. We hypothesised that placental vessels dictate fetoplacental resistance and in FGR exhibit endothelial dysfunction and reduced flow‐mediated vasodilatation (FMVD). Resistance was measured in normal pregnancies ( n = 10) and FGR ( n = 10) both in vivo by umbilical artery Doppler velocimetry and ex vivo by dual placental perfusion. Ex vivo FMVD is the reduction in fetal‐side inflow hydrostatic pressure (FIHP) following increased flow rate. Results demonstrated a significant correlation between vascular resistance measured in vivo and ex vivo in normal pregnancy, but not in FGR. In perfused FGR placentas, vascular resistance was significantly elevated compared to normal placentas (58 ± 7.7 mmHg and 36.8 ± 4.5 mmHg, respectively; 8 ml min −1; means ± SEM; P < 0.0001) and FMVD was severely reduced (3.9 ± 1.3% and 9.1 ± 1.2%, respectively). In normal pregnancies only, the highest level of ex vivo FMVD was associated with the lowest in vivo resistance. Inhibition of NO synthesis during perfusion (100 μ m l‐NNA) moderately elevated FIHP in the normal group, but substantially in the FGR group. Human placenta artery endothelial cells from FGR groups exhibited increased shear stress‐induced NO generation, iNOS expression and eNOS expression compared with normal groups. In conclusion, fetoplacental resistance is determined by placental vessels, and is increased in FGR. The latter also exhibit reduced FMVD, but with a partial compensatory increased NO generation capacity. The data support our hypothesis, which highlights the importance of FMVD regulation in normal and dysfunctional placentation.

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          Most cited references56

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          Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia.

          The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production. These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.
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            Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage.

            Tonic basal release of nitric oxide (NO) by vascular endothelial cells controls blood pressure (BP) in the basal state. In these studies we investigated the effects of chronic inhibition of basal NO synthesis in the rat for a 2-mo period. Significant systemic hypertension developed in chronically NO-blocked rats compared to controls. Marked renal vasoconstriction was also observed with elevations in glomerular blood pressure (PGC) and reductions in the glomerular capillary ultrafiltration coefficient (Kf). Chronically NO-blocked rats also develop proteinuria and glomerular sclerotic injury compared to controls. These studies therefore describe a new model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous NO synthesis. These observations highlight the importance of the endogenous NO system in control of normal vascular tone and suggest that hypertensive states may result from relative NO deficiency.
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              Developmental biology of the placenta and the origins of placental insufficiency.

              Defects in all the trophoblast-differentiating pathways--endovascular, interstitial and chorionic villous--play a role in the pathogenesis of early-onset intra-uterine growth restriction (IUGR). There are two types of extravillous trophoblast: endovascular trophoblast, that forms the definitive placenta by occlusion of the spiral arteriole at the implantation site, and interstitial extravillous trophoblast, responsible for the anatomical erosion of the distal spiral arteriole and the secretion of angiogenic and vasodilator signals to improve uterine blood flow. Defective endovascular erosion may render the basal plate inadequate to meet the demands of the fetus. Failed interstitial invasion of spiral arterioles could lead to failure of local angiogenic and systemic cardiovascular adaptation signals that could be the underlying basis for early-onset IUGR and pre-eclampsia. As debate persists regarding the relative importance of cord, stem and terminal villous pathology, the study of factors controlling trophoblast turnover from immature intermediate villi to conductance stem villi and gas-exchanging terminal villi, translation of our knowledge from mouse placental genetics into human placental development, and defining causes of thrombo-occlusive damage to the placenta would help our understanding of the pathophysiology of early-onset IUGR.
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                Author and article information

                Journal
                J Physiol
                J. Physiol. (Lond.)
                10.1111/(ISSN)1469-7793
                TJP
                jphysiol
                The Journal of Physiology
                John Wiley and Sons Inc. (Hoboken )
                0022-3751
                1469-7793
                08 June 2015
                15 July 2015
                : 593
                : 14 ( doiID: 10.1113/jphysiol.2015.593.issue-14 )
                : 3077-3092
                Affiliations
                [ 1 ]Maternal and Fetal Health Research Centre, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, St. Mary's Hospital, Oxford Road Manchester M13 9WLUK
                [ 2 ]Maternal and Fetal Health Research Centre, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre Manchester M13 9WLUK
                [ 3 ]Institute of Cell Biology, Histology and Embryology, Medical University of Graz GrazAustria
                [ 4 ]Department of Obstetrics and Gynecology, Medical University of Graz GrazAustria
                Author notes
                [*] [* ] Corresponding author P. Brownbill: Maternal and Fetal Health Research Centre, University of Manchester, 5th Floor, St Mary's Hospital, Manchester M13 9WL, UK.   Email: paul.brownbill@ 123456manchester.ac.uk
                Article
                TJP6669
                10.1113/JP270495
                4532528
                25920377
                9da750c4-ed00-474b-8fc6-084751ccd524
                © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society

                Open access.

                History
                : 21 November 2014
                : 22 April 2015
                Page count
                Pages: 16
                Funding
                Funded by: British Heart Foundation
                Award ID: PG/11/11/28725
                Categories
                Research Paper
                Cardiovascular
                Custom metadata
                2.0
                tjp6669
                15 July 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.7.6 mode:remove_FC converted:03.02.2016

                Human biology
                Human biology

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