Vasoactive mediator release by fetal endothelial cells in intrauterine growth restriction and preeclampsia (original) (raw)
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Hypertension in Pregnancy, 1999
Objective: We investigated the hypothesis that changes in blood flow in the uteroplacental and fetoplacental circulation in preeclampsia are associated with an abnormality of placental or uterine placental bed nitric oxide (NO) synthesis. Merhods: We measured pulsatility indices on Doppler waveform analysis from uterine and umbilical arteries in 20 patients with preeclampsia and 14 healthy pregnant controls before elective cesarean section. During cesarean section, biopsies from the uterine placental bed and the placenta were taken and the nitric oxide synthase (NOS) activity was measured by the ['HI L-arginine-[ " H ] L-citrulline conversion assay in these samples. Results: The NOS activity was significantly lower in the uterine placental bed in comparison to the placental tissue (p < 0.01).
Regulation of human placental fetal vessel tone: role of nitric oxide
Reproduction, Fertility and Development, 1995
Factors affecting fetal vessel resistance have been studied in vitro in bilaterally perfused lobules of human placentae. Potent and efficacious constrictors in this preparation (in order of potency) include endothelin-1 > the thromboxane mimetic U46619 > endothelin-3 > prostaglandin F2 alpha. Inhibitors of eicosanoid synthesis did not affect fetal vessel basal perfusion pressure, nor did they potentiate the effects of the vasoconstrictor U46619. In contrast, the nitric oxide inhibitors N omega-nitro-L-arginine (NOLA), haemoglobin and methylene blue all increased fetal vessel basal perfusion pressure and also increased U46619-induced constriction. Similarly, NOLA markedly potentiated the constrictor effects of endothelin-1, angiotensin II, 5-hydroxytryptamine and bradykinin. These studies therefore provide evidence that NO is important in the maintenance of low basal fetal vessel impedance and also reduces the effects of a number of vasoconstrictor autacoids. Nitric oxide sy...
Reduction of Placental Nitric Oxide Synthase Activity in Pre-Eclampsia
Clinical Science, 1997
The role of the potent vasodilator nitric oxide in the pathogenesis of pre-eclampsia is unclear. We have tested the hypothesis that placental activity of the enzyme which synthesizes nitric oxide (nitric oxide synthase) is reduced in pre-eclampsia. 2. Placentae were obtained after vaginal delivery or Caesarean section from women who had been assigned to the following groups according to standard obstetric criteria: term non-pre-eclamptic control, term pre-eclamptic, preterm non-preeclamptic control and preterm pre-eclamptic. Nitric oxide synthase activity of placental tissue homogenates was assessed by measuring conversion of r3H] L-arginine into [3H] L-citrulline in the presence of NADPH, FAD, tetrahydrobiopterin, calmodulin, CaC12, magnesium acetate and a range of L-arginine concentrations. Michaelis Menton constants (K,) amd maximum velocities of reaction (Vmax) were calculated using Lineweaver-Burk analysis. 3. Vmax was significantly reduced in both term and preterm pre-eclamptic placentae compared with placentae from corresponding gestation-matched controls. There were no significant differences in the Km values for nitric oxide synthase between any of the four groups, nor were Vmsx or K , values significantly influenced by mode of delivery. 4. These results provide evidence that human placental nitric oxide synthase activity is significantly reduced in pre-eclampsia. Such a reduction was evident at both term and preterm gestations. Reduced placental nitric oxide synthase activity may have an adverse effect on placental haemodynamic function in pre-eclampsia, and could be involved in the pathogenesis of this important and common obstetric complication.
Histopathology, 2004
Preeclampsia is associated with loss of neuronal nitric oxide synthase expression in vascular smooth muscle cells of the human umbilical cord Aims: Umbilical blood vessels are not innervated and regulation of blood flow to the placenta must depend on structural changes and the effect of vasoactive factors. Failure to achieve these adaptations may result in reduced fetoplacental perfusion. The purpose of this study was to determine whether neuronal nitric oxide synthase (nNOS) is expressed in human vascular smooth muscle cells (VSMCs) of the fetoplacental circulation. nNOS has been described as a nonendothelial NOS counterregulating vasoconstriction only in the VSMCs of animal models. Therefore, we investigated nNOS expression in the fetoplacental unit from preeclamptic and healthy pregnancies. Methods and results: We investigated nNOS regulation by immunohistochemistry, Western blotting and reverse transcriptase-polymerase chain reaction analysis. nNOS activity was determined by measuring the conversion of L-3 H-arginine to L-3 H-citrulline. nNOS expression was revealed only in VSMCs of the human umbilical veins, but not in umbilical arteries. A more direct assessment of nNOS activity showed that a small, but consistent amount of nNOS is present in the denuded media of the umbilical vein. In VSMCs of the umbilical veins during preeclampsia a total loss of nNOS protein expression and a significant decrease in mRNA expression were seen. Conclusions: Loss of nNOS expression is associated with preeclampsia. It may alter the regulation of blood flow in the fetal and maternal placental vasculature in preeclampsia. However, the impact of NO produced by nNOS on the vascular tone of umbilical veins remains to be elucidated.
Compensatory feto-placental upregulation of the nitric oxide system during fetal growth restriction
PloS one, 2012
Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system. Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12). Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric di...
Maternal and Fetal Complications Due to Decreased Nitric Oxide Synthesis during Gestation
Complications of Pregnancy, 2019
Nitric oxide (NO) is synthesized from L-arginine by the constitutive NO synthase in vascular endothelial cells and plays an important role in the regulation of blood pressure and coronary vasomotion. Normal pregnancy is associated with major adaptations in maternal cardiovascular function, which help the woman to accommodate the growing fetus. The vascular endothelium is stimulated during pregnancy to release increased amounts of NO, and the abnormality in the L-arginine NO pathway may play a role in the etiology of preeclampsia. The objective of this study is to discuss the importance of nitric oxide during gestation and the maternal and fetal complications associated with decreased NO synthesis during this period. Maternal arterial hypertension due to inhibition of nitric oxide synthesis during pregnancy impairs fetal development, mainly the reduction of the wall/lumen ratio of the cardiac and renal microvasculature as well as the reduction in the number of nephrons. These changes...
The FASEB Journal, 2002
Preeclampsia (PE) is a leading cause of maternal hypertension in pregnancy, fetal growth restriction, premature birth, and fetal and maternal mortality (1). Activation and dysfunction of the maternal and fetal endothelium in PE may be the consequence of increased oxidative stress associated with circulating lipid peroxides (2-4), and in cases of severe maternal hypertension, uterine and umbilical artery waveforms are abnormal (5). We have investigated PE-associated abnormalities in the regulation of intracellular Ca 2+ ([Ca 2+ ] i ) and cyclic guanosine monophosphate (cGMP) production (index of nitric oxide [NO]) in human fetal umbilical vein endothelial cells. Basal [Ca 2+ ] i was slightly elevated in PE cells, whereas agonist-stimulated Ca 2+ entry was reduced in cells from PE compared with normal term or age-matched preterm pregnancies. Furthermore, PE cells exhibited a decreased permeability to Ba 2+ but an increased permeability to Mn 2+ and Gd 3+ , suggesting that PE is associated with phenotypic alterations in fetal endothelial cation channel(s). Basal and histamine-stimulated cGMP levels were elevated in PE compared with preterm or normal cells, implying an increased NO production in PE. However, immunoblots for endothelial NO synthase (eNOS) and soluble guanylyl cyclase (sGC) revealed reduced eNOS expression in PE and preterm cells, with negligible changes in sGC levels. This study provides important and novel insights into abnormalities of fetal endothelial cells isolated from women with PE, revealing an altered cation membrane permeability and activity of eNOS-sGC pathway. As these changes are sustained in culture in vitro, this may reflect long-term "programming" of the fetal cardiovascular system.