Placental Vascularization Research Articles

Upregulation of Urotensin II Receptor in Preeclampsia Causes In Vitro Placental Release of Soluble Vascular Endothelial Growth Factor Receptor 1 in Hypoxia

Preeclampsia is a hypertensive disorder of pregnancy caused by abnormal placental function, partly because of chronic hypoxia at the utero-placental junction. The increase in levels of soluble vascular endothelial growth factor receptor 1, an antiangiogenic agent known to inhibit placental vascularization, is an important cellular factor implicated in the onset of preeclampsia. We investigated the ligand urotensin II (U-II), a potent endogenous vasoconstrictor and proangiogenic agent, for which levels have been reported to increase in patients with preeclampsia. We hypothesized that an increased sensitivity to U-II in preeclampsia might be achieved by upregulation of placental U-II receptors. We further investigated the role of U-II receptor stimulation on soluble vascular endothelial growth factor receptor 1 release in placental explants from diseased and normal patients. Immunohistochemistry, real-time PCR, and Western blotting analysis revealed that U-II receptor expression was significantly upregulated in preeclampsia placentas compared with controls (P<0.01). Cellular models of syncytiotrophoblast and vascular endothelial cells subjected to hypoxic conditions revealed an increase in U-II receptor levels in the syncytiotrophoblast model. This induction is regulated by the transcriptional activator hypoxia-inducible factor 1alpha. U-II treatment is associated with increased secretion of soluble vascular endothelial growth factor receptor 1 only in preeclamptic placental explants under hypoxia but not in control conditions. Interestingly, normal placental explants did not respond to U-II stimulation.

Histomorphometric characteristics of first trimester chorionic villi in pregnancies with low serum pregnancy-associated plasma protein-A levels: relationship with placental three-dimensional power doppler ultrasonographic vascularization

Objective. To evaluate histomorphometric vascular characteristics from samples obtained by chorionic villus sampling (CVS) in pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) levels and to relate these findings to three-dimensional (3D) placental volume and power Doppler vascularization.Methods. Immediately before CVS, placental 3D-power Doppler ultrasonography was performed at 11 + 0 to 13 + 6 weeks in 12 pregnancies with PAPP-A concentrations <0.3 multiples of median (MoM) as well as in 11 control women. Using a standardized setting placental volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured. Histomorphometric parameters of villi were blindly evaluated with a video-computerized-image-analysis system.Results. Pregnancies with low PAPP-A showed a significantly reduced number of capillary vessels per villus cross-section (p = 0.005) and a smaller capillary diameter (p = 0.041). Placental vascular indices were significantly related to the number of fetal capillary vessels per villus (VI: r = 0.51, p = 0.03; FI: r = 0.48, p = 0.04; VFI: r = 0.56, p = 0.01).Conclusions. Differences in placental vascularization are present in first trimester in pregnancies with low PAPP-A and they are associated to altered 3D placental Doppler indices.

Maternal obesity and overnutrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe

In pregnant sheep, maternal:fetal exchange occurs across placentomes composed of placental cotyledonary and uterine caruncular tissues. Recently, we reported that fetal weights of obese (OB) ewes [fed a diet of 150% of National Research Council (NRC) recommendations] were approximately 30% greater than those of control (C) ewes (fed a diet 100% of NRC recommendations) at midgestation (MG), but fetal weights were similar in late gestation (LG). Transplacental nutrient exchange is dependent on placental blood flow, which itself is dependent on placental vascularity. The current study investigated whether the observed initial faster and subsequent slower fetal growth rate of OB compared with C was associated with changes in cotyledonary vascularity and expression of angiogenic factors (vascular endothelial growth factor, fibroblast growth factor-2, placental growth factor, angiopoietin-1 and -2). Cotyledonary arteriole diameters were markedly greater (P < 0.05) in OB than C ewes at MG, but while arteriole diameter of C ewes increased (P < 0.05) from MG to LG, they remained unchanged in OB ewes. Cotyledonary arterial angiogenic factors mRNA and protein expression were lower (P < 0.05) in OB than C ewes at MG and remained low from MG to LG. In contrast, mRNA levels of angiogenic factors in C ewes declined from high levels at MG to reach those of OB ewes by LG. The increase in cotyledonary arteriole diameter in early to MG may function to accelerate fetal growth rate in OB ewes, while the decreased cotyledonary arterial angiogenic factors from MG-LG may function to protect the fetus from excessive placental vascular development, increased maternal nutrient delivery, and excessive weight gain.

Lipoprotein (a), Birth Weight and Neonatal Stroke

Background: Elevated lipoprotein (Lp) (a) is the most common genetically determined risk factor found in babies with perinatal ischemic stroke. The influence of maternal Lp(a) has not been studied extensively to date. Objectives: To investigate the role of Lp(a) in our population of neonates with stroke. Methods: In a prospective uncontrolled cohort of term-born children with neonatal arterial ischemic stroke, Lp(a) levels were investigated in 69 mothers and 69 children. Paternal Lp(a) was not explored. Results: An increased Lp(a) level was found in 26 mothers [38%; 95% confidence interval (CI) 28–50%] and in 15 children (22%; 95% CI 13–33%). Both rates were higher than the reference range reported in the general Caucasian population (10% in adults and 5% in children). Additionally, there was a correlation between maternal and infantile Lp(a) levels (p < 0.0001) and between elevated maternal Lp(a) level and lower birth weight (p = 0.027). Conclusions: Elevated maternal Lp(a) is apparently a risk factor for neonatal arterial ischemic stroke. We speculate that the pathological mechanism of this relation may be mediated through a dysfunction of the placental vascularization.

An assessment of vascularity and flow intensity of the placenta in normal pregnancy and pre-eclampsia using three-dimensional ultrasound

Objective. To test the hypothesis that parameters of vascularity and flow intensity of the placenta as determined by three-dimensional (3D) ultrasound, (1) are different in normal pregnancy compared to pre-eclampsia (2) decrease from the basal plate towards the chorionic plate.Methods. Twenty women with normal pregnancy and 17 women with pre-eclampisa were studied. 3D power Doppler ultrasound was used to acquire individual placental volumes. Rotational measurements of placental volumes were acquired using virtual organ computer aided analysis (VOCAL™). The power Doppler signals were then semi-quantified within ‘histogram facility’, which generates three vascularity and flow intensity parameters: flow index (FI), vascular index (VI) and vascularisation flow index (VFI).Results. FI, VI and VFI were lower in pre-eclampsia compared to normal pregnancy in all regions of the placenta. This difference was statistically significant in most regions of the placenta after accounting for gestational age, body mass index and placental site. We were not able to demonstrate a decreasing gradient of these parameters from basal plate to chorionic plate.Conclusion. 3D ultrasound to assess placental vascularity and flow intensity appears to be an interesting research tool. However, other indices derived from Power Doppler may be more relevant to obstetric practice.

Validation of Placental Vascular Sonobiopsy for Obtaining Representative Placental Vascular Indices by Three-Dimensional Power Doppler Ultrasonography

Objective Placental vascular sonobiopsy has been proposed for obtaining a representative sample of the placental vascular tree when evaluation of the whole placenta is not feasible. We tested the hypothesis that placental vascular indices from sonobiopsy correlate well with those from the entire placenta. Methods Three-dimensional power Doppler ultrasound examinations were performed in 120 singleton pregnancies at 11–14 weeks' gestation. The VOCAL™ program was used to calculate placental vascularization index (VI), flow index (FI) and vascularization flow index (VFI) from stored images of each placenta by whole placenta evaluation and placenta vascular sonobiopsy. The mean of each index from four spherical sonobiopsies were compared to those from evaluation of the entire placenta for their degree of correlation and agreement. Results The mean VI and VFI from the two techniques were similar (13.9 [95% CI 12.3–15.8] versus 14.3 [95% CI 12.1–17.0], p = 0.62 and 6.1 [95% CI 5.2–7.1] versus 6.1 [95% CI 5.0–7.4], p = 0.93, respectively) and significantly correlated (Pearson's r = 0.70 [95% CI 0.60–0.78, p < 0.001] and r = 0.69 [95% CI 0.58–0.77, p < 0.001], respectively). The mean FI from the two techniques were significantly different (44.5 [95% CI 42.9–46.1] versus 41.3 [95% CI 39.6–43.0], p = 0.001), but correlated ( r = 0.59 [95% CI 0.46–0.70, p < 0.001]). Conclusion Our findings suggest that placenta vascular indices from sonobiopsy have a good correlation with those from evaluation of the entire placenta. Sonobiopsy may be a valid alternative for evaluation of the placental vascular tree when visualization of the entire placenta is not feasible. Measurements of VI and VFI appear to be more reliable than FI in sonobiopsy specimen.

316. MATERNAL DIETARY ARGININE SUPPLEMENTATION DURING LATE GESTATION IMPROVES REPRODUCTIVE EFFICIENCY IN PIGS

Arginine (a non-essential amino acid) and its conversion to nitric oxide (NO) can promote formation of new blood vessels and cause vasodilation. This may reduce resistance and increase blood flow to the uterus and placenta, and the delivery of nutrients for fetal growth and survival. In pregnant rats, dietary arginine deficiency causes IUGR and increases fetal death and perinatal mortality, whereas dietary arginine supplementation reverses this. Human IUGR is associated with impaired NO synthesis, and eNOS activity in umbilical vein endothelial cells, but maternal arginine supplements have produced inconclusive results. We hypothesised that maternal arginine supplementation (MAS) in the pig (a species with naturally occurring IUGR), during late gestation, when placental angiogenesis and vascularity increase, would increase birth and placental weights. Large White (LW) and Landrace (LR) gilts (n = 285) and sows (n = 326), were fed either a control or arginine supplemented (+25 g/d arginine, Nutreco Progenos premix) diet (2.5 kg/d) in late gestation (d75-term at ~114 days). Number born, born alive, still born and mummified, birth weight and d10 weight of progeny were measured. Data were analysed using Univariate ANOVA. MAS in late gestation in gilts and sows reduced the number of still born (Con: 1.17 ± 0.13 piglets/litter; Arg: 0.84 ± 0.09 piglets/litter; P = 0.046). In LW gilts, MAS increased birth weight (Con: 1.21 ± 0.05kg; Arg: 1.34 ± 0.05kg; P &lt; 0.05), and litter birth weight (Con: 13.38 ± 0.72 kg; Arg: 15.27 ± 0.73 kg; P &lt; 0.05). MAS also increased birth weight in LW (Con: 1.17 ± 0.06 kg; Arg: 1.30 ± 0.06 kg; P &lt; 0.05) and LR (Con: 1.47 ± 0.05 kg; Arg: 1.60 ± 0.05 kg; P &lt; 0.05) sows, and reduced still borns in LW sows (Con: 1.12 ± 0.14 piglets/litter; Arg: 0.77 ± 0.09 piglets/litter; P &lt; 0.05). MAS in late gestation improves pregnancy outcomes in terms of piglet survival and birth weight, in LW and LR gilts and sows. MAS during critical periods of placental development may enhance placental-fetal blood flow and nutrient transfer, thereby improving fetal growth and survival.

Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy

During human and nonhuman primate pregnancy, an extensive blood vessel network is established within the villous placenta to support fetal growth and follicles develop within the fetal ovary to provide a pool of oocytes for reproductive function in adulthood. These two important developmental events occur in association with a progressive increase in placental estrogen production and levels. This review will describe the developmental processes required for placental vascularization and fetal follicular maturation and recent studies which show that estrogen has an important role in regulating these events.

Placental blood flow measured by three-dimensional power Doppler ultrasound at 26 to 35 weeks gestation in normal pregnancies

Objective. To evaluate placental vascular indices, in pregnancies between 26 and 35 weeks, using three-dimensional power Doppler (3DPD) ultrasound and the effect of placental location on these indices.Methods. This was a cross-sectional study involving 283 patients. The placental vascularization index (VI), flow index (FI) and vascularization and flow index (VFI) was obtained using the VOCAL program. Pearson's linear correlation coefficient was used to assess the relationship between gestational age and these indices. Student's parametric t-test and Levene's test were used to analyse the results between VI, FI and VFI and placental location.Results. There was no linear correlation between gestational age (GA) and VI (p = 0.390) and VFI (p = 0.053). Only the FI presented a significant linear correlation (p = 0.004), with a slow increase according to GA. It was possible to construct a reliable nomogram only for this index. There were no significant differences in the VI, FI and VFI according to placental location (p = 0.323, 0.172 and 0.120, respectively).Conclusion. Placental FI assessed by 3DPD increases progressively and significantly between 26 and 35 weeks. Placental location has no influence on the three vascular indices studied. The FI reference values obtained in this study can be used as a parameter for future investigations on placental vascularization using 3DPD.

First-Trimester Placental Volume and Vascularization Measured by 3-Dimensional Power Doppler Sonography in Pregnancies With Low Serum Pregnancy-Associated Plasma Protein A Levels

The purpose of this study was to investigate the first-trimester placental volume and 3-dimensional (3D) power Doppler vascularization of pregnancies with low serum pregnancy-associated plasma protein A (PAPP-A) levels and to relate these findings to pregnancy outcomes. Three-dimensional power Doppler sonography of the placenta was performed at gestational ages of 11 weeks to 13 weeks 6 days in 84 pregnancies with PAPP-A concentrations of less than 0.4 multiple of the median (MoM). With a standardized setting, the placental volume and vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were calculated and related to pregnancy outcomes. Pregnancy outcomes were as follows: 57 pregnancies with birth weights at or above the 10th percentile (group A), 16 pregnancies with birth weights below the 10th percentile and normal Doppler findings in the umbilical artery throughout gestation (group B), and 11 pregnancies with birth weights below the 10th percentile and abnormal umbilical Doppler findings later in gestation (group C). No differences were found in PAPP-A levels among groups. Placental volume values were significantly lower than reference limits, but no differences were found between groups. In groups A and B, there were no significant differences in 3D Doppler indices. However, these indices were significantly lower in group C (VI mean difference, -1.904; P < .001; FI mean difference, -1.939; P < .001; VFI mean difference, -1.944; P < .001). Placental vascular indices were significantly related to the severity of intrauterine growth restriction (IUGR; VI, r = 0.438; P < .001; FI, r = 0.482; P < .001; VFI, r = 0.497; P < .001) but not to the PAPP-A MoM and placental volume values. Low serum maternal PAPP-A levels are associated with altered 3D placental Doppler indices, and these changes are related to subsequent development of IUGR and adverse pregnancy outcomes.

Reproducibility of First Trimester Three-dimensional Placental Measurements in the Evaluation of Early Placental Insufficiency

ObjectiveTo evaluate the reproducibility of first-trimester, three-dimensional placental volume and vasculature evaluation by ultrasound in correlation with uterine artery Doppler flow studies. MethodWe performed a prospective study of a cohort of pregnant women undergoing first-trimester ultrasound examination. Uterine artery Doppler and 3-D power Doppler angiography was performed. Placental volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were calculated three times by two independent observers using the virtual organ computer-aided analysis (VOCAL) software. Intra- and interobserver reproducibility was evaluated by Spearman’s correlation test. All parameters between women with low (< 1.5 multiple of median) (MoM) and high (> 1.5 MoM) uterine artery Pourcelot index (PI) were compared by the Mann-Whitney test. ResultsA total of 35 women between 11 and 14 weeks’ gestation were recruited, including 26 who underwent uterine artery Doppler and six with elevated uterine artery PI. We found excellent intraand interobserver reproducibility (R2 > 0.85) for all parameters. Women with elevated uterine artery PI had smaller placental volume, VI, FI, and VFI (P < 0.05). Conclusion3-D placental volume and vasculature evaluations during the first trimester are reproducible measures that inversely correlate with uterine artery PI.

775: The effects of cigarette smoke on cell viability and angiogenic factors in a cytotrophoblast cell line

Smoking has been associated with alterations in genes responsible for controlling angiogenesis and placental vascularization important in preeclampsia, such as soluble fms-like tyrosine kinase (sFlt-1), adrenomedullin (ADM), and vascular endothelial growth factor (VEGF). The objective of this investigation was to determine if cigarette smoke extract (CSE) exposure to a trophoblast cell line was associated with cell proliferation and differences in RNA expression of these genes.

Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy

In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.

P194 The benefits of 3D Power Doppler ultrasound in assessment of placental vascularisation

International Journal of Gynecology & ObstetricsVolume 107, Issue S2 p. S467-S467 Poster presentations P194 The benefits of 3D Power Doppler ultrasound in assessment of placental vascularisation C. Mihu, C. MihuSearch for more papers by this authorD. Mihu, D. MihuSearch for more papers by this authorN. Costin, N. CostinSearch for more papers by this authorM. Oancea, M. OanceaSearch for more papers by this authorA. Malutan, A. MalutanSearch for more papers by this author C. Mihu, C. MihuSearch for more papers by this authorD. Mihu, D. MihuSearch for more papers by this authorN. Costin, N. CostinSearch for more papers by this authorM. Oancea, M. OanceaSearch for more papers by this authorA. Malutan, A. MalutanSearch for more papers by this author First published: 20 November 2009 https://doi.org/10.1016/S0020-7292(09)61685-4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume107, IssueS2Abstracts of XIX FIGO World Congress of Gynecology and ObstetricsOctober 2009Pages S467-S467 RelatedInformation

OC16.02: Inter-observer reliability of quantitative 3D power Doppler angiography of whole placental vascularity

3D power Doppler angiography (3DPDA) allows quantification of blood flow within the placenta. The aim of this study was to investigate the interobserver reproducibility of quantitative 3DPDA as a tool to assess placental vascularity. Subjects were scanned at 12, 16 and 20 weeks gestations with a Voluson 730 Expert. 3DPD data were acquired from the whole placenta and analysed using VOCAL and 9 degree rotation steps. Each image was analysed by three observers who made two measurements in the transverse (B) plane. Interobserver reliability was assessed by two-way mixed intraclass correlation coefficients (ICCs) and Bland–Altman plots estimated the level of agreement between the observers. 52 low risk women were scanned at varying gestations resulting in 30 subjects at each gestation and 90 datasets in total. The ICC for data analysis demonstrated a high level of measurement reliability at each gestation: ICC 0.871, 0.968 and 0.980 for VI; 0.911, 0.924 and 0.958 for FI; 0.981, 0.959 and 0.977 for VFI at 12, 16 and 20 weeks gestation. Bland–Altman plots showed a progressive reduction in the agreement between the observers with increasing gestation. This study demonstrates that 3DPDA data can be measured by different observers to produce a quantitative analysis of whole placental vasculature. Measurements become less reliable as gestation advances.

OP29.04: Placental vascularization by three-dimensional power Doppler in the twin-to-twin transfusion syndrome

OP29.04: Placental vascularization by three-dimensional power Doppler in the twin-to-twin transfusion syndrome

P07.05: Placental vascularization by three-dimensional power Doppler at 7 to 10 weeks of pregnancy

P07.05: Placental vascularization by three-dimensional power Doppler at 7 to 10 weeks of pregnancy

OC16.03: Quantifying placental vascularity: evaluating the intraobserver reliability of 3D power Doppler data acquisition and measurement of the whole placenta

3D power Doppler angiography (3DPDA) allows quantification of blood flow within the placenta. The aim of this study was to investigate the interobserver reproducibility of quantitative 3DPDA as a tool to assess placental vascularity. Subjects were scanned at 12, 16 and 20 weeks gestations with a Voluson 730 Expert. 3DPD data were acquired from the whole placenta and analysed using VOCAL and 9 degree rotation steps. Each image was analysed by three observers who made two measurements in the transverse (B) plane. Interobserver reliability was assessed by two-way mixed intraclass correlation coefficients (ICCs) and Bland–Altman plots estimated the level of agreement between the observers. 52 low risk women were scanned at varying gestations resulting in 30 subjects at each gestation and 90 datasets in total. The ICC for data analysis demonstrated a high level of measurement reliability at each gestation: ICC 0.871, 0.968 and 0.980 for VI; 0.911, 0.924 and 0.958 for FI; 0.981, 0.959 and 0.977 for VFI at 12, 16 and 20 weeks gestation. Bland–Altman plots showed a progressive reduction in the agreement between the observers with increasing gestation. This study demonstrates that 3DPDA data can be measured by different observers to produce a quantitative analysis of whole placental vasculature. Measurements become less reliable as gestation advances.

P23.11: First trimester three dimensional placental vasclar indices in women at risk of placental insufficiency: a preliminary study

Objective: To compare three dimensional placental vascular indices between pregnant women at risk of placental insufficiency and a control group. Material and Methods: Seventeen pregnant women with singleton pregnancies allocated into two groups (10 at risk of placental insufficiency and 7 controls) were scanned at 12 weeks of gestation. VOLUSON 730 Expert (GE) with VOCAL software and histogram facility was used. Flow index (FI), vascular index (VI) and vascular flow index (VFI) were calculated. Measurements were done at both 0.9 and 2.4 kHz. Student t test was used for comparisons. Results: There were no differences between the two groups in terms of maternal age, body mass index or placental location. Women at risk of placental insufficiency had significant higher values of VFI at 0.9 kHz of PRF (p = 0.02). VI at 0.9 kHz was also higher in the risk group but at borderline significance level (p = 0.07). Conclusions: Using low PRF values, increased placental vascularization is detected in women at risk of placental insufficiency. A longer follow up of these women is needed to clarify whether or not this finding is clinically useful to identify women who are going to develop placental disease.

P07.06: The relationships between body mass index and first trimester placental volume and vascularization

P07.06: The relationships between body mass index and first trimester placental volume and vascularization