In utero hypoxia attenuated acetylcholine-mediated vasodilatation via CHRM3/p-NOS3 in fetal sheep MCA: role of ROS/ERK1/2.

Hypoxia can lead to adult middle cerebral artery (MCA) dysfunction and increase the risk of cerebrovascular diseases. It is largely unknown whether intrauterine hypoxia affects fetal MCA vasodilatation. This study investigated the effects and mechanisms of intrauterine hypoxia on fetal MCA vasodilatation. Near-term fetal sheep were exposed to intrauterine hypoxia. Human umbilical vein endothelial cells (HUVECs) were exposed to hypoxia in cellular experiments. Vascular tone measurement, molecular analysis, and transmission electron microscope (TEM) were utilized to determine vascular functions, tissue anatomy, and molecular pathways in fetal MCA. In fetal MCA, acetylcholine (ACh) induced reliable relaxation, which was markedly attenuated by intrauterine hypoxia. Atropine, P-F-HHSiD, L-NAME, and u0126 blocked most ACh-mediated dilation, while AF-DX 116 and tropicamide partially inhibited the dilation. Indomethacin and SB203580 did not significantly change ACh-mediated dilation. Tempol and PS-341 could restore the attenuated ACh-mediated vasodilatation following intrauterine hypoxia. The mRNA expression levels of CHRM2 and CHRM3 and the protein levels of CHRM3, p-NOS3, SOD2, ERK1/2, p-ERK1/2, MAPK14, and p-MAPK14 were significantly reduced by intrauterine hypoxia. The dihydroethidium assay showed that the production of ROS was increased under intrauterine hypoxia. TEM analysis revealed endothelial cells damaged by intrauterine hypoxia. In HUVECs, hypoxia increased ROS formation and decreased the expression of CHRM3, p-NOS3, SOD1, SOD2, SOD3, ERK1/2, p-ERK1/2, and p-MAPK14, while tempol and PS-341 potentiated p-NOS3 protein expression. In conclusion, in utero hypoxia reduced ACh-mediated vasodilatation in ovine MCA predominantly via decreased CHRM3 and p-NOS3, and the decreased NOS3 bioactivities might be attributed to ROS and ERK1/2.

The effect of maternal position on fetal middle cerebral artery Doppler indices and its association with adverse perinatal outcomes: a pilot study.

Objective The aim of this study was to compare position-related changes in fetal middle cerebral artery (MCA) Doppler pulsatility indices (PI). Methods A prospective study of 41 women with conditions associated with placental-pathology (chronic hypertension, pregestational diabetes, and abnormal analytes) and 34 women without those conditions was carried out. Fetal MCA Doppler velocity flow waveforms were obtained in maternal supine and left lateral decubitus positions. MCA PI Δ was calculated by subtracting the PI in the supine position from the PI in the left lateral position. Secondary outcomes included a composite of adverse perinatal outcomes (fetal growth restriction, oligohydramnios, and preeclampsia). χ2 and Student t-tests and repeated-measures analysis of variance were used. Results MCA PI Δ was significantly less for high-risk pregnant women ([P = 0.03]: high risk, left lateral PI, 1.90 ± 0.45 vs. supine PI, 1.88 ± 0.46 [Δ = 0.02]; low risk, left lateral PI, 1.90 ± 0.525 vs. supine PI, 1.68 ± 0.40 [Δ = 0.22]). MCA PI Δ was not significantly different between women who had a composite adverse outcome and women who did not have a composite adverse outcome (P = 0.843). Conclusion Our preliminary study highlights differences in position-related changes in fetal MCA PI between high-risk and low-risk pregnancies. These differences could reflect an attenuated ability of women with certain risk factors to respond to physiologic stress.

Reference Ranges of Doppler Indices in the Fetal Middle Cerebral Artery according to Gestational Age / 대한산부인과학회잡지

OBJECTIVES: To investigate the "brain sparing effect", a paradoxical increase in fetal cerebral perfusion in pregnant women with uteroplacental insufficiency through fetal middle cerebral artery(MCA) waveform analysis, and to construct new reference ranges for fetal MCA Doppler flow velocity resistance indices in nomal preganacies to be used in the assessment of fetal well-being. MATERIALS AND METHODS: The subjects were selected from pregnant women receiving antenatal care at Severance Hospital between March 1996 and December 1999. Fetal MCA reference resistance index range according to gestational age were obtained through routine Doppler velocimetry for 4621 normal pregnant women between 24-42 gestational weeks. Those manifesting multiple pregnancy, Diabetes Mellitus, drug abuse, chronic hypertension, fetal congenital anomaly, fetal growth restriction(FGR) with discrepencies of more than 7days and pregnancies complicated by pregnancy induced hypertension (PIH) were excluded. Additionally, the fetal MCA hemodynamic changes were compared for 140 pregnant women with FGR or PIH. The normal ranges for fetal MCA Doppler resistance indices were expressed as mean+/-SD, and a comparative analysis between the PIH or FGR group and the normal control group was performed. Statistical analysis was done using the SPSS 8.0 program, t-test and the Pearson correlation. RESULT: The fetal MCA doppler flow resistance indices for normal pregnancies were 0.77+/-0.006 at 24 weeks and 0.79+/-0.006 at 28 weeks, demonstrating a statistically significant increase(p<0.05). At 40 weeks the index was 0.71+/-0.009 showing a significant decrease after 28weeks(p<0.05). There was a tendency for the resistance index to be lower in the PIH/FGR group compared to the normal controls. CONCLUSION: Constructing a normal reference resistance index range for fetal MCA flow is of high clinical value with regards to predicting fetal well being and understanding the hemodynamics of fetal cerebral perfusion.