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The Correlation of UtA Volume Blood Flow Measured by Transit Time Flow Probes With Measurement by Doppler Sonography, With Time-Averaged Maximum Velocity and With UtA Vessel Area, Using the Pearson Correlation Coefficient a
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Accurate noninvasive quantification of volume blood flow in the uterine arteries (UtAs) would have clinical and research benefits. We evaluated the correlation and agreement between uterine artery volume blood flow (UtABF) as calculated (cUtABF) from color/pulsed-wave Doppler acquisitions and that measured (mUtABF) by bilateral perivascular transit...
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Citations
... Although the fetal compartment in small ruminants has been monitored transabdominally [11][12][13] and after surgery and instrumentation [14], invasive techniques have been chosen for the investigation of blood flow parameters in uterine arteries [15][16][17][18][19]. Only recently, a transabdominal approach in anesthetized animals after surgical mobilization of the arteries was reported [20,21]. Sequential noninvasive investigations throughout pregnancy are missing. ...
... This is the first report of a noninvasive color Doppler technique to sequential assessment of the maternal blood throughout gestation in sheep and goats. Previous studies used stains [34,35] radionuclide-labeled microspheres [36] or surgically implanted electromagnetic flow probes [20,21,37]. In the latter case occasionally combined with single transabdominal Doppler scans of the mobilized and marked vessel. ...
... Although the fetal compartment in small ruminants has been monitored transabdominally111213 and after surgery and instru- mentation [14], invasive techniques have been chosen for the investigation of blood flow parameters in uterine arteries1516171819. Only recently, a transabdominal approach in anesthetized animals after surgical mobilization of the arteries was reported [20,21]. Sequential noninvasive investigations throughout pregnancy are missing. ...
... This is the first report of a noninvasive color Doppler technique to sequential assessment of the maternal blood throughout gestation in sheep and goats. Previous studies used stains [34,35] radionuclide-labeled microspheres [36] or surgically implanted electromagnetic flow probes [20,21,37]. In the latter case occasionally combined with single transabdominal Doppler scans of the mobilized and marked vessel. ...
... Other authors have estimated the flow rate to the sheep fetus to be 603 ml/min between 124 and 136 days of gestation (around 208 ml/ kg/min) [17]. The physiologic uterine artery flow, measured by Doppler in a pregnant sheep with a twin pregnancy at the end of gestation, is around 500–900 ml/min (per uterine artery) [18]. We did not calculate a fixed flow rate for our uteri but used a SvO 2 goal and titrated the ECMO flow to achieve this. ...
Background
Previous models of support for premature sheep fetuses have consisted of cesarean delivery followed by catheterization of umbilical or central vessels and support with extracorporeal membrane oxygenation (ECMO). The limitations of these models have been insufficient blood flow, significant fetal edema, and hemorrhage related to anticoagulation.
Methods
We performed a gravid hysterectomy on 13 ewes between 135 and 145 days gestational age. The uterine vessels were cannulated bilaterally and circulatory support was provided via ECMO. Successful transition was defined as maintenance of fetal heart rate for 30 minutes after establishing full extracorporeal support. Circuit flow was titrated to maintain mixed venous oxygen saturation (SvO2) of 70–75%.
Results
Seven experiments were successfully transitioned to ECMO, with an average survival time of 2 hours 9 minutes. The longest recorded time from cannulation to death was 6 hours 14 minutes. By delivering a circuit flow of up to 2120 ml/min, all but one of the transitioned uteri were maintained within the desired SvO2 range.
Conclusion
We report a novel animal model of fetal ECMO support that preserves the placenta, mitigates the effects of heparin, and allows for increased circuit flow compared to prior techniques. This approach may provide insight into a technique for future studies of fetal physiology.
... For long term experiments, a transit time flow probe (6 mm 6PS, Transonic Systems Inc., NY, USA), which can measure blood flow with an absolute accuracy of 610% was placed around the main UtA on each side. The cabling from each probe was then exteriorized onto the ewe's right flank, and the skin buttons were secured to the skin as described [19]. The abdomen was closed, the ewe received standard analgesia and antibiotic prophylaxis and the animal was then recovered. ...
... Ad.LacZ vector (5610 11 viral particles in 10 ml phosphate buffered saline) was injected into the contralateral UtA. The ewe received standard analgesia and antibiotic prophylaxis, and the abdominal incision was closed [19]. ...
Background:
The normal development of the uteroplacental circulation in pregnancy depends on angiogenic and vasodilatory factors such as vascular endothelial growth factor (VEGF). Reduced uterine artery blood flow (UABF) is a common cause of fetal growth restriction; abnormalities in angiogenic factors are implicated. Previously we showed that adenovirus (Ad)-mediated VEGF-A165 expression in the pregnant sheep uterine artery (UtA) increased nitric oxide synthase (NOS) expression, altered vascular reactivity and increased UABF. VEGF-D is a VEGF family member that promotes angiogenesis and vasodilatation but, in contrast to VEGF-A, does not increase vascular permeability. Here we examined the effect of Ad.VEGF-DΔNΔC vector encoding a fully processed form of VEGF-D, on the uteroplacental circulation.
Methods:
UtA transit-time flow probes and carotid artery catheters were implanted in mid-gestation pregnant sheep (n = 5) to measure baseline UABF and maternal haemodynamics respectively. 7-14 days later, after injection of Ad.VEGF-DΔNΔC vector (5×10(11) particles) into one UtA and an Ad vector encoding β-galactosidase (Ad.LacZ) contralaterally, UABF was measured daily until scheduled post-mortem examination at term. UtAs were assessed for vascular reactivity, NOS expression and endothelial cell proliferation; NOS expression was studied in ex vivo transduced UtA endothelial cells (UAECs).
Results:
At 4 weeks post-injection, Ad.VEGF-DΔNΔC treated UtAs showed significantly lesser vasoconstriction (Emax144.0 v/s 184.2, p = 0.002). There was a tendency to higher UABF in Ad.VEGF-DΔNΔC compared to Ad.LacZ transduced UtAs (50.58% v/s 26.94%, p = 0.152). There was no significant effect on maternal haemodynamics. An increased number of proliferating endothelial cells and adventitial blood vessels were observed in immunohistochemistry. Ad.VEGF-DΔNΔC expression in cultured UAECs upregulated eNOS and iNOS expression.
Conclusions:
Local over-expression of VEGF-DΔNΔC in the UtAs of pregnant mid-gestation sheep reduced vasoconstriction, promoted endothelial cell proliferation and showed a trend towards increased UABF. Studies in cultured UAECs indicate that VEGF-DΔNΔC may act in part through upregulation of eNOS and iNOS.
... The calculated uterine artery volume blood fl ow (cUtABF) is derived using the formula: cUtABF (ml/min) = TAMEAN-V(cm/s) × A(cm 2 ) ×60, where the vessel area is calculated as A = p ( D /2) 2 assuming the vessel to have a circular lumen. The time-averaged intensity-weighted mean velocity (TAMEAN-V) is calculated by multiplying TAMAX-V by 0.6, which is the spatial velocity distribution coef fi cient derived in the sheep uterine arteries( 26 ) . ...
So far no systematic studies have been conducted to investigate developmental aberrations after prenatal gene transfer in mice. Here, we suggest procedures for such observations to be applied, tested and improved in further in utero gene therapy experiments. They are based on our own experience in husbandry for transgenic human diseases mouse models and breading, rearing, and observing mice after fetal gene transfer as well as on the systematic screens for monitoring of knock-out mutant mouse phenotypes established in international mutagenesis projects (EUMORPHIA and EUMODIC and subsequently the International Mouse Phenotyping Consortium).
We also describe here the analysis procedures for detection of germ line mutations based on quantitative PCR (qPCR) by sperm-DNA analysis and breeding studies.
... Importantly, the use of the 'gold standard' transit-time flow probes in this study, instead of Doppler ultrasonography 28 as used in our previous short-term study, provides a far more accurate and reliable estimate of the true increase in UABF. 29 To our knowledge, this is the first report of a single intervention that leads to a sustained increase in UABF within or outside of pregnancy. There are currently no other interventions that have successfully achieved a long-term increase in UtA perfusion. ...
... The cabling from each probe was then exteriorized onto the ewe's right flank, and the skin buttons were secured to the skin as described. 29 After 4 to 10 days (at 97.82±2.37 days of gestation), the sheep underwent a second general anesthetic and laparotomy for local administration of Ad.VEGF-A 165 and Ad.LacZ vectors into the UtAs contralaterally. The viral dose administered was 5 Â 10 11 viral particles in 10 ml PBS, over a 5-min period during which the UtA was digitally occluded proximal to the site of injection. ...
... The ewe received standard analgesia and antibiotic prophylaxis, and the abdominal incision was closed. 29 Two ewes (1 singleton and 1 twin) received injection of PBS (10 ml) instead of adenovirus vector into each UtA to act as a sham injection control group, providing data for maternal hemodynamic assessment and tissues for organ bath experiments and other analyses. In the ewes where fetal hemodynamic monitoring was performed, UABF data were not measured (Table 1). ...
Increasing uterine artery blood flow (UABF) may benefit fetal growth restriction where impaired uteroplacental perfusion prevails. Based on previous short-term results, we examined the long-term effects of adenovirus vector-mediated overexpression of vascular endothelial growth factor-A(165) (VEGF-A(165)) in the uterine artery (UtA). Transit-time flow probes were implanted around both UtAs of mid-gestation pregnant sheep (n=11) to measure UABF. A carotid artery catheter was inserted to measure maternal or fetal hemodynamics. Baseline UABF was measured over 3 days, before injection of adenovirus vector (5 × 10(11) particles) encoding the VEGF-A(165) gene (Ad.VEGF-A(165)) into one UtA and a reporter β-galactosidase gene (Ad.LacZ) contralaterally. UABF was then measured daily until term. At 4 weeks post injection, the increase in UABF was significantly higher in Ad.VEGF-A(165) compared with Ad.LacZ-transduced UtAs (36.53% vs 20.08%, P=0.02). There was no significant effect on maternal and fetal blood pressure. Organ bath studies showed significantly lesser vasoconstriction (E(max) 154.1 vs 184.7, P<0.001), whereas immunohistochemistry demonstrated a significantly increased number of adventitial blood vessels (140 vs 91, n=26, P<0.05) following Ad.VEGF-A(165) transduction. Local overexpression of VEGF-A(165) in the UtAs of pregnant mid-gestation sheep leads to a sustained long-term increase in UABF, which may be explained by neovascularization and altered vascular reactivity.
Introduction:
Severe fetal growth restriction (FGR) affects 1:500 pregnancies, is untreatable and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) and lack of bioavailable VEGF due to placental insufficiency is a major cause. Transduction of uterine arteries in normal or FGR sheep and guinea pigs using an adenovirus (Ad) encoding VEGF isoforms A (Ad.VEGF-A165) and a FLAG-tagged pre-processed short form D (DΔNΔC, Ad.VEGF-DΔNΔC-FLAG) increases endothelial nitric oxide expression, enhances relaxation and reduces constriction of the uterine arteries and their branches. UBF and angiogenesis are increased long term, improving fetal growth in utero. For clinical trial development we compared Ad.VEGF vector transduction efficiency and function in endothelial cells (ECs) derived from different species.
Objective:
To compare the transduction efficiency and function of the pre-clinical study Ad. constructs (Ad.VEGF-A165, Ad.VEGF-DΔNΔC-FLAG) with the intended clinical trial construct (Ad.VEGF-DΔNΔC) where the FLAG tag is removed.
Methods:
We infected ECs from human umbilical vein, pregnant sheep uterine artery, pregnant guinea pig aorta and non-pregnant rabbit aorta, with increasing multiplicity of infection (MOI) for 24 or 48 hours of three Ad.VEGF vectors, compared to control Ad. containing the LacZ gene (Ad.LacZ). VEGF supernatant expression was analysed by ELISA. Functional assessment used tube formation assay and Erk-Akt phosphorylation by ELISA.
Results:
VEGF expression was higher after Ad.VEGF-DΔNΔC-FLAG and Ad.VEGF-DΔNΔC transduction compared to Ad.VEGF-A165 in all EC types (*p<0.001). Tube formation was higher in ECs transduced with Ad.VEGF-DΔNΔC in all species compared to other constructs (***p<0.001, *p<0.05 with rabbit aortic ECs). Phospho-Erk and phospho-Akt assays displayed no differences between the three vector constructs, whose effect was, as in other experiments, higher than Ad.LacZ (***p<0.001).
Conclusion:
We observed high transduction efficiency and functional effects of Ad.VEGF-DΔNΔC vector with comparability in major pathway activation to constructs used in pre-clinical studies, supporting its use in a clinical trial.
Objectives:
To investigate the relationship between total uterine artery blood volume flow rate (TVFR) and birth weight and gestational age at delivery, and to establish normal ranges of TVFR throughout pregnancy.
Methods:
This was a prospective cohort study of 334 nulliparous women booking antenatal care at University College London Hospital between August 2008 and September 2009. Women underwent a transabdominal ultrasound examination of uterine arteries for measurement of TVFR at 12, 20 and 24 weeks' gestation. Pregnancy outcomes were recorded and linear regression was used to study the relationship between TVFR and gestational age at delivery and birth weight.
Results:
A total of 551 ultrasound scans were performed. There was a significant, positive correlation between TVFR at 11-13 weeks (TVFR1) and at 22-26 weeks (TVFR3) and birth weight. For every 100-mL/min increase in TVFR1 and TVFR3, there was an increase in birth weight of 45 g and 27 g, respectively. There was also a positive association between TVFR1 and gestational age at delivery, with a 1.4-day increase in gestational age for every 100-mL/min increase of TVFR1.
Conclusion:
Ultrasound measurement of TVFR in the first trimester is significantly associated with both birth weight and gestational age at delivery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Introduction: An adverse intrauterine environment may program the fetus for metabolic and cardiovascular disease in childhood and later in life. In particular, the ability of the maternal supply line to provide oxygen and nutrients to the growing placenta and fetus represents a key factor determining fetal outcome. The placenta constitutes the interface between the maternal and fetal circulations, serving as an immune barrier as well as the organ for exchange and metabolism of nutrients between mother and fetus. The placenta also controls maternal metabolism during pregnancy by secreting a variety of hormones into the maternal circulation. A large number of studies has now shown that variations in maternal diet (amount and composition) can alter fetal growth and/or development and program the fetus for later disease. In order to affect the fetus, perturbations in maternal nutrient availability must be transmitted across the placenta and there is an increasing awareness that the placenta responds to and modulates changes in the ability of the mother to provide nutrients. Therefore, the placenta is in a powerful position to influence fetal development by changes in expression and activity of, for example, specific nutrient transporters that affect fetal growth. Altered fetal growth (intrauterine growth restriction [IUGR] and fetal overgrowth) in human pregnancy is associated with specific changes in placental amino acid transporters, which may cause changes in fetal growth rate and mediate programming of the fetus.
We shall not cease from exploration And the end of all our exploring Will be to arrive where we started And know the place for the first time. Introduction: In keeping with the theme of this book, this chapter explores a critical aspect of fetal programming; namely the determinants of uterine blood flow and their role in fetoplacental development. This important topic has been the subject of investigation for more than 50 years. Early studies were begun by Donald Barron and his distinguished team in the 1950s in Peru, and at about the same time by John Lichty and co-workers in Colorado. These studies combined with later work done by our and other groups have firmly established that high altitude restricts fetal growth and therefore serves as a valuable study design for investigating the determinants of fetoplacental development. The lessons learned from these studies are reviewed here, including current work investigating the physiological and genetic mechanisms regulating uterine oxygen delivery. This chapter closes with a brief discussion of areas likely to be fruitful for future research. Early studies Normal fetoplacental development requires adequate and sustained tissue delivery of oxygen. Given the lower barometric pressure and the resultant decline in the partial pressure of oxygen, high altitude has served as a natural laboratory for studying the effects of hypoxia on fetoplacental development.
