Placental Perfusion Research Articles

Impact of ductus arteriosus constriction and restrictive foramen ovale on global hemodynamics for term fetuses with d-TGA.

The ductus arteriosus (DA) constriction and restrictive foramen ovale (FO) are known as the leading cause of compromise and death of fetuses with dextro-transposition of the great arteries (d-TGA). Although the d-TGA fetal hemodynamics is of great importance in making diagnosis and management of the congenital heart defect, it remains poorly understood, particularly in terms of abnormal DA and FO. In this study, we developed a closed-loop 0-1D multiscale model of the fetal cardiovascular system (CVS) specified for the d-TGA circulation and conducted a systematic study of the impact of the DA constriction and restrictive FO on fetal hemodynamics. We found that the DA constriction led to a pronounced increase in the pulmonary artery pressure, pulmonary and mitral valve (PV and MV) regurgitation as well as left heart volume; the restrictive FO was responsible for reducing MV E/A ratio, ie, the ratio of peak early filling and late diastolic filling velocities, and PV peak systolic flow (PSV) but could increase both aortic valve (AV) PSV and aortic isthmus systolic index (ISI). Moreover, the amount of blood flowing through the DA was observed equivalent to that through the FO; the influence of DA constriction on the cerebral and placental perfusions are larger than that of the FO. Our results demonstrate that the proposed fetal cardiovascular model may be a useful tool for studying the underlying mechanisms associated with d-TGA fetal circulation and providing insights into its complex physiology and pathology.

Identification and quantification of gold engineered nanomaterials and impaired fluid transfer across the rat placenta via ex vivo perfusion

Development and implementation of products incorporating nanoparticles are occurring at a rapid pace. These particles are widely utilized in domestic, occupational, and biomedical applications. Currently, it is unclear if pregnant women will be able to take advantage of the potential biomedical nanoproducts out of concerns associated with placental transfer and fetal interactions. We recently developed an ex vivo rat placental perfusion technique to allow for the evaluation of xenobiotic transfer and placental physiological perturbations. In this study, a segment of the uterine horn and associated placenta was isolated from pregnant (gestational day 20) Sprague-Dawley rats and placed into a modified pressure myography vessel chamber. The proximal and distal ends of the maternal uterine artery and the vessels of the umbilical cord were cannulated, secured, and perfused with physiological salt solution (PSS). The proximal uterine artery and umbilical artery were pressurized at 80 mmHg and 50 mmHg, respectively, to allow countercurrent flow through the placenta. After equilibration, a single 900 μL bolus dose of 20 nm gold engineered nanoparticles (Au-ENM) was introduced into the proximal maternal artery. Distal uterine and umbilical vein effluents were collected every 10 min for 180 min to measure placental fluid dynamics. The quantification of Au-ENM transfer was conducted via inductively coupled plasma mass spectrometry (ICP-MS). Overall, we were able to measure Au-ENM within uterine and umbilical effluent with 20 min of material infusion. This novel methodology may be widely incorporated into studies of pharmacology, toxicology, and placental physiology.

First trimester placental volume is reduced in hypertensive disorders of pregnancy associated with small for gestational age fetus

Introduction Trophoblastic invasion and placental growth are critical for pregnancy outcome. The placental volume can be assessed by 3 D ultrasound using Virtual Organ Computer-aided Analysis (VOCAL). Epidemiological and clinical data suggest that there are two different clinical phenotypes of hypertensive disorders of pregnancy (HDP) that coexist at any gestational age: HDP associated to fetal growth impairment and HDP associated to appropriate for gestational age fetal growth. The aim of this study was to determine whether placental volume in the first trimester of pregnancy differs between women with HDP associated or not to fetal growth impairment and uncomplicated pregnancies. Methods This is a retrospective cross-sectional study of prospectively recruited data in which maternal characteristics, Doppler velocimetry of uterine arteries, and three-dimensional (3 D) volume of the placenta were collected at 11 + 1 − 13 + 6 gestational weeks. The placental quotient (PQ) was calculated as placental volume/crown rump length. Results In a 2-year period, we prospectively collected first trimester data of 1322 women. For the purposes of this cross-sectional study, 57 women that delivered a SGA fetus, 34 that developed HDP-AGA, and six that developed HDP-SGA, respectively, were included in the study as cases. The control group was made of 117 uncomplicated pregnancies. The PQ was higher in women with uncomplicated pregnancies (PQ median 16.36 cm3/cm) than in all other study groups (PQ in SGA: 13.02 cm3/cm, p < .001; PQ in HDP-AGA: 12.65 cm3/cm, p = .002; and PQ in women with HDP-SGA: 8.33 cm3/cm [IQR 6.50–10.13], p < .001). The lowest PQ was observed in women with HDP-SGA and was significantly lower than PQ in either women with SGA or those with HDP-AGA (p = .02 and p = .04, respectively). The mean uterine artery pulsatility index was the highest in women with HDP-SGA (median 2.30) compared to all other groups (uncomplicated pregnancies 1.48, p < .0001; women with SGA 1.59, p = .001; and women with HDP-AGA 1.75, p = .009). Discussion Our findings suggest that HDP associated with SGA is characterized by impaired placental growth and perfusion as soon as in the first trimester of pregnancy. The role of PQ, isolated or in association with other biophysical parameters, to predict HDP with fetal growth impairment remains to be evaluated.

Characterisation of the Selective Reduced Uteroplacental Perfusion (sRUPP) Model of Preeclampsia

Preeclampsia is a complication of pregnancy characterised by gestational hypertension, proteinuria and/or end organ disease. The reduced uteroplacental perfusion (RUPP) model, via partial occlusion of the lower abdominal aorta, mimics insufficient placental perfusion as a primary causal characteristic of preeclampsia. However, a major limitation of the RUPP model is that perfusion is reduced to the entire hindquarters of the rat resulting in hindlimb ischemia. We hypothesised that clipping the uterine and ovarian arteries in the selective (s)RUPP model would provoke signs of preeclampsia while avoiding systemic ischemia. Sham, RUPP or sRUPP procedures were performed in pregnant Sprague Dawley rats on gestational day (GD)14. On GD21 uterine blood flow was significantly reduced in both the RUPP and sRUPP models while aortic flow was reduced only in RUPP. Both models resulted in increased MAP, increased vascular oxidative stress (superoxide generation), increased pro-inflammatory (RANTES) and reduced pro-angiogenic (endoglin) mediators. Vascular compliance and constriction were unaltered in either RUPP or sRUPP groups. In summary, refinements to the RUPP model simultaneously maintain the characteristic phenotype of preeclampsia and avoid peripheral ischemia; providing a useful tool which may be used to increase our knowledge and bring us closer to a solution for women affected by preeclampsia.

Preeclampsia: The Relationship between Uterine Artery Blood Flow and Trophoblast Function.

Maternal uterine artery blood flow is critical to maintaining the intrauterine environment, permitting normal placental function, and supporting fetal growth. It has long been believed that inadequate transformation of the maternal uterine vasculature is a consequence of primary defective trophoblast invasion and leads to the development of preeclampsia. That early pregnancy maternal uterine artery perfusion is strongly associated with placental cellular function and behaviour has always been interpreted in this context. Consistently observed changes in pre-conceptual maternal and uterine artery blood flow, abdominal pregnancy implantation, and late pregnancy have been challenging this concept, and suggest that abnormal placental perfusion may result in trophoblast impairment, rather than the other way round. This review focuses on evidence that maternal cardiovascular function plays a significant role in the pathophysiology of preeclampsia.

Socio-economic Status Associated with Normotensive and Pre-eclamptic Women in Bangladesh

Pre-eclampsia is a disorder of 2nd half of pregnancy, which is characterized by a combination of hypertension, proteinuria and edema; secondary to decreased placental perfusion. It is commonly associated with reduced weight, diameter and volume of placenta, along with other microscopic changes. This was a comparative study, of 220 pregnant women, selected with inclusion and exclusion criteria from 3 different medical colleges - Dhaka Medical College and Hospital, Sir Salimullah Medical College and Milford Hospital and Holy Family Red Crescent Medical College and Hospital. The objective of this study is to see the association of sods economic status of selected normotensive and pre-eclamptic women in Bangladesh. Those 220 cases were then divided into 2 groups - a study group, consisting of 110 pre-eclamptic women and a control group consisting of 110 normotensive pregnant women. The sample size was determined using the standard formula. The study was then explained to each individual subject and informed consent was taken. Standard pretested questionnaire was used to collect necessary information regarding their age, residential status, educational background, occupation, age of marriage, monthly income, dietary information and nutritional status. All interviews were conducted in the hospital. Dietary information was collected by 7 days food frequency questionnaire and food score was determined. Anthropometric and biochemical tests were carried out. Urinary protein was evaluated by the Heat Coagulation test. It was found that majority of the pre-eclamptic women were in the age group of 18-24 (56.36%) years, semi-urban (70.90%), housewives (56.36%), and 45.45% of the women could write. Almost half of the pre- eclamptic group (49.09%) had a monthly income of 25,000 to 29,999 taka.

Human Placental Vascular Reactivity in Health and Disease: Implications for the Treatment of Pre-eclampsia.

Adequate development of the placenta is essential for optimal pregnancy outcome. Pre-eclampsia (PE) is increasingly recognized to be a consequence of placental dysfunction and can cause serious maternal and fetal complications during pregnancy. Furthermore, PE increases the risk of neonatal problems and has been shown to be a risk factor for cardiovascular disease of the mother later in life. Currently, there is no adequate treatment for PE, mainly because its multifactorial pathophysiology remains incompletely understood. It originates in early pregnancy with abnormal placentation and involves a cascade of dysregulated systems in the placental vasculature. To investigate therapeutic strategies it is essential to understand the regulation of vascular reactivity and remodeling of blood vessels in the placenta. Techniques using human tissue such as the ex vivo placental perfusion model provide insight in the vasoactive profile of the placenta, and are essential to study the effects of drugs on the fetal vasculature. This approach highlights the different pathways that are involved in the vascular regulation of the human placenta, changes that occur during PE and the importance of focusing on restoring these dysfunctional systems when studying treatment strategies for PE.

Dengue haemorrhagic fever in late pregnancy causing maternal and intrauterine foetal death – A case report

Dengue during pregnancy carries a higher risk of maternal and foetal complications, either through haemodynamic instability from disruption of the placental perfusion or through vertical transmission to the foetus. A previously healthy 29-year-old primigravidae with a POA of 34 weeks presented with one day fever to a tertiary hospital. NS 1 antigen for dengue was positive. She entered the critical phase the following day and her platelet count dropped to 3000/ml by day 3. Intra uterine death was diagnosed on day 4. She continuously deteriorated and died on day 7. At autopsy, gross bleeding manifestations were noted in the mother, along with bilateral pleural effusions, massive sub endocardial haemorrhages and an enlarged liver with sub capsular haemorrhages. The placenta was devoid of any haemorrhages or infarcts. Sub-aponeurotic and subarachnoid haemorrhages and 50ml of blood within the thoracic and peritoneal cavities were found in a mature female foetus with minimal signs of maceration. Laboratory confirmation of foetal dengue virus infection was not possible. This is a rare case where fatal haemorrhagic manifestations were seen in both the mother and the foetus suggesting vertical transmission. The autopsy findings highlight the unpredictable haemodynamic changes in the uterine circulation which severely hinder dengue management during pregnancy. Dengue infection, especially in late pregnancy, can lead to unpredictable fatal outcomes. The potential benefit of performing an emergency caesarean in such cases should be further explored.

Association among ACE, ESR1 polymorphisms and preeclampsia in Brazilian pregnant women

BackgroundGenetic, immune and environmental factors are involved in preeclampsia (PE) etiopathogenesis. Considering that hypertension and poor placental perfusion are important features in PE, polymorphisms in the angiotensin-converting enzyme (ACE) and estrogen nuclear receptor 1 (ESR1) genes could be involved in the predisposition and/or development of the disease. The aim of this study was to evaluate if polymorphisms in ACE and ESR1 genes were associated with PE occurrence. Material and MethodsThis case-control study included 209 Brazilian pregnant women (107 with severe PE and 102 normotensive controls). The polymorphisms were investigated by polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis. ResultsNo significant difference between PE versus normotensive pregnant women, as well as early versus late PE, was observed when compared the allelic and genotypic frequencies of insertion/deletion polymorphism in intron 16 of the ACE gene and the single nucleotide polymorphisms (SNPs - rs2234693 and rs9340799) of the ESR1 gene. ConclusionThis pioneer study involving Brazilian women showed no association among the studied polymorphisms and PE, which suggests that ins/del ACE and SNPs ESR1 do not contribute to this disease occurrence in Brazil.

SUN-LB060 Paraganglioma in Pregnancy: Challenges to Treatment

Background: Paragangliomas are rare neuroendocrine tumors that arise from extra-adrenal chromaffin cells derived from the embryonic neural crest. Sympathetic paragangliomas secrete catecholamines and present with episodic hypertension and tachycardia. Paragangliomas in pregnancy are extremely rare. Here we describe a complicated case of a paraganglioma in pregnancy that highlights the special considerations taken during this state. Case Presentation: A 17-year-old pregnant female presented with chest pain and dyspnea on exertion at 32 weeks of gestation secondary to hypertensive urgency. Further history revealed several paternal family members with tumors and resistant hypertension. A work-up for secondary causes of hypertension was performed. Pertinent studies included plasma normetanephrines >50 nmol/L (0-0.89 nmol/L) and normal plasma metanephrines. Plasma fractionated catecholamines revealed a norepinephrine level of 18,977 pg/mL (85-1250 pg/mL), a dopamine level of 83 pg/mL (0-20 pg/mL), and a normal epinephrine level. MRI revealed an 8.0 cm hyperintense left infrarenal mass consistent with a paraganglioma. The patient was started on increasing doses of phenoxybenzamine followed by metoprolol to reduce her blood pressure and heart rate, keeping placental perfusion in mind. At 35 weeks of gestation she underwent successful cesarean delivery immediately followed by surgical resection of the tumor. Pathology revealed a 9.1 cm mass with nests of tumor cells, prominent vascularity, and foci of necrosis. A periaortic lymph node infiltrated by tumor indicated malignancy. Immunostaining was positive for neuron specific enolase, chromogranin, and synaptophysin. The patient briefly required vasopressors post-operatively, but she and the neonate recovered well with intensive monitoring. Genetic testing revealed a mutation in the succinate dehydrogenase B gene, increasing her risk for recurrent malignant paragangliomas and necessitating genetic testing of her child. Conclusions: Paragangliomas discovered during pregnancy are extraordinarily rare and present several challenges to management. While alpha and beta blockade should be initiated to correct volume depletion and avoid hemodynamic lability, caution must be taken to avoid excessive reductions in blood pressure and heart rate that may precipitate uteroplacental insufficiency and intrauterine growth restriction. Cesarean delivery is preferred over vaginal delivery to reduce the risk of precipitating hypertensive crisis. Furthermore, phenoxybenzamine crosses the placenta and neonates should be monitored in the NICU for hypotension in the first few days of life. Lastly, as approximately one quarter of all paragangliomas are associated with a genetic mutation, it is imperative to discuss genetic testing with the patient and the implications of a positive result for both the patient and offspring. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SUN-077 In Utero Growth Restriction Induces an Early Metabolic Shift in Fetal Rat Heart

Adverse uterine environment may expose newborns to develop metabolic diseases later in their life. The in-utero growth restriction (IUGR) is an immediate outcome of a sub-optimal womb environment, where the fetus cannot reach its full growth potential. We have developed an animal model of IUGR based on a low-sodium diet given to dams during the last week of gestation. We showed that the isocaloric low-sodium diet reduces maternal blood volume expansion, causing poor placental perfusion, low placental weight and subsequent IUGR in offspring. Redistribution of blood flow in the fetus was observed, causing a preferential perfusion to major organs, such as the heart. Consistent with this, adult offspring showed an increase in blood pressure and remodeling of cardiomyocytes occurs in adult female, suggesting metabolic changes in cardiac function. In this study, we address whether the IUGR induced-stress leads to metabolic changes in fetal cardiomyocytes to adapt their energy-production process and lipid utilization. At 22 days of gestation, hearts were collected from IUGR and control fetuses, and homogenized. Gene expression profile as well as protein levels were analyzed. We observed an increased expression of critical genes involved in lipid metabolism, such as long chain fatty acid receptor CD36, carnitine palmitoyltransferase CPT1a, and also key enzymes of long chain fatty acid beta-oxidation in IUGR heart. In addition, our results indicate an increase in mitochondrial biogenesis. To address whether changes in lipid metabolite profile might prevail, we performed lipidomic MS analysis in heart homogenates. Lipidomics showed significant accumulation of very long and long-chain fatty acids in the context of IUGR and when comparing males and females. These changes could be reminiscent of an adaptation in the use of fatty acids for energy production. Altogether, these findings suggest that fetal IUGR cardiac cells may rely more on the use of lipids as an energy source, compared to same age control cells. Such alterations in energy metabolism in fetal IUGR cardiomyocytes are consistent with an early metabolic shift to favor lipids as the main energy source. This shift normally occurs in the neonatal life to adapt to an extra-uterine environment. Therefore, our findings suggest that adaptation to an altered placental perfusion results in an early cardiac metabolic remodeling that might predispose individuals to metabolic disorders later in their life. Sources of Research Support: Fond de Recherche Québécois en Santé (FRQS) and Canadian Institutes of Health Research (CIHR).

H2S Improves the Rate of Migration in Trophoblast Cells

IntroductionThe migration of trophoblast cells during the first trimester of pregnancy is crucial to placentation process. Defective migration of trophoblastic cells may affect the remodelling (pseduovasculogenesis) of spiral arteries resulting in Hypoxia/Reoxygenation (H/R) episodes. These repeated H/R events can leads to oxidative stress and release of anti‐angiogenic, anti‐inflammatory and pro‐oxidant factors in maternal circulation causing endothelial dysfunction resulting in adverse pregnancy outcomes like preeclampsia and fetal growth restriction. The anti‐inflammatory, pro‐angiogenic and pro‐migratory effect of H2S on endothelial cells have been documented in literature. So we hypothesized that H2S or its mimics (NaHS) may also affect the migration capacity of trophoblast cells during placentation.MethodsThe immortalized first trimester extravillous trophoblast cell line (HTR‐8/SVneo) were given various treatments like 50μM NaHS, Hypoxia/Reoxygenation [H/R (one and two cycles)] and Hypoxia/Reoxygenation supplemented with 50μM NaHS. The cell migration was assessed using wound scratch assay following these various exposures. The percentage wound area covered was assessed in all groups. The difference in wound covered area was statistically analysed. [ten different zone in triplicate (i.e. thirty) were used for calculating the wound areas]ResultsThe percentage of wound covered area (rate of migration) increased in cells which received 50μM NaHS [control (32.8%), NaHS (67.5%)] whereas it reduced to 8.7% in Hypoxia/Reoxygenation one cycle exposed cells and more so (−18.9%) in the cells which received two cycles of Hypoxia/Reoxygenation. However the cells which received Hypoxia/Reoxygenation (one cycle and two cycles) and showed reduced migration, improved their rate of migration when supplemented with 50μM NaHS. [one cycle H/R (8.7%), one cycle H/R+NaHS (39.8) and two cycles H/R (−18.9%), two cycles H/R+NaHS (29.5%)]. The difference in wound covered area among various groups was statistically significant [(control vs NaHS; p&lt;0.001, control vs one cycle H/R; p&lt;0.001, control vs two cycle H/R; p&lt;0.001, one cycle H/R vs one cycle H/R+NaHS; p &lt;0.001, two cycle H/R vs two cycles H/R+NaHS; p&lt;0.001 (one‐way ANOVA with Bonferroni correction)].ConclusionThese results imply that H2S may promote the migration of trophoblastic cells, which might then lead to adequate conversion of spiral arteries into wider diameter low resistance vessels having good placental perfusion. In future the role of H2S on cellular and molecular factors responsible for cell migration needs to explored.IESC/T‐467/23.12.2014Support or Funding InformationF.8‐397/A‐397/2015/RsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Comparative Study between Nifedipine, Ritodrine and Magnesium Sulfate as Tocolytics in Cases of Preterm Labor and Their Effect on Utero Placental Perfusion

Background: in the developed world, preterm birth (PTB) is a major problem in modern obstetrics; its prevalence is still rising in many industrialized countries. Early PTB (before 34 weeks) is particularly associated with high rates of mortality and morbidity. Aim of the Work: to compare the efficacy of oral nifedipine, intra venous ritodrine and magnesium sulfate as tocolytics in cases with preterm labor and evaluate their effects on the utero placental perfusion in order to choose the safest and most cost-effective drug. Patients and Methods: a prospective study that was conducted in El sayed Galal and El Hussien University hospitals from November 2016 to November 2018. By identifying 150 pregnant women with gestational age from 24-37 weeks gestation with preterm labour pain, intact membranes, singleton pregnancy. Results: a statistically significant difference was found between groups according to fetal umbilical artery PI before and after treatment. Also, significant difference between before and after treatment according to fetal umbilical artery PI in magnesium sulfate group. Also a statistically significant difference between groups according to fetal middle cerebral artery PI before and after treatment. Also, significant difference between before and after treatment according to fetal middle cerebral artery PI in nifedipine and magnesium sulfate group. Conclusion: there was no overall difference between nifedipine, magnesium sulfate and ritodrine, in their efficacy as tocolytic for preterm labor. However, Nifedipine had fewer maternal side effects followed by magnesium sulfate than ritodrine. Irrespective of their tocolytic effects, magnesium sulfate has the most significant effect on Doppler study.

Substitution of Casein Dietary Protein with Wheat Gluten Protein Protects Dahl Salt Sensitive Rats from the Development of Maternal Syndrome

Previously our group demonstrated that the maternal diet of the Dahl Salt‐Sensitive (SS) rat, specifically the protein source, during gestation and lactation can impact the severity of salt sensitive hypertension and renal damage of the offspring in adulthood. Offspring born from mothers fed a wheat gluten‐based diet exhibited blunted salt‐sensitive hypertension and renal damage when compared to offspring born from casein fed mothers. Utilizing an embryo transfer approach we determined that regardless of whether an embryo originated from parents fed a casein or a wheat gluten‐based diet, the diet of the surrogate mother that determined the severity of salt‐sensitivity in the offspring. In addition to the maternal diet, the in utero environment has been shown to contribute to the programming of lifelong health of offspring. Dahl SS rats maintained on a casein‐based diet (SSC) develop maternal syndrome (hypertension and proteinuria) compared to virgin controls. Since offspring from mothers fed a wheat gluten based diet were protected from SS hypertension and the Dahl SSC rat develops maternal syndrome, we tested the hypothesis that mothers fed a wheat gluten (SSWG) diet will be protected from the development of maternal syndrome. To test this hypothesis Dahl SSWG and SSC rats were studied on their respective diets, which are identical in every aspect except for the protein source. At 8 weeks of age, females were instrumented with radio‐telemeters for continuous measurement of mean arterial pressure (MAP). After a recovery period, baseline MAP was measured as well as an overnight urine collection for markers of renal damage before females were mated with males of the same age and diet. Virgin littermate controls of the same age and diet for each strain were run in parallel. During the baseline period, there was no difference observed in MAP or protein excretion rate among any of the groups. As previously reported, the SSC mated rats develop an increase in MAP (141±3 vs 129±3 mmHg, p&lt;0.05) and protein excretion rate (98±16 vs 46±5 mg/day, p&lt;0.05) at gestational day 20 (GD) compared to virgin controls. Interestingly, there was a significant reduction in MAP in the SSWG mated rats compared to SSWG virgin controls at GD20 (114±4 vs 126±4 mmHg, respectively, p&lt;0.05). Comparing the SSC and SSWG mated rats at GD20, it is evident that the SSWG mated rats are protected from developing maternal syndrome seen in the SSC mated rats (MAP: 114±4 vs 141±3 mmHg, p&lt;0.001, Proteinuria: 52±12 vs 98±16 mg/day, p&lt;0.01). Additionally, uterine artery resistance index, which is utilized as a surrogate marker for placental perfusion, is significantly greater in the SSC rats compared to the SSWG at GD20 (0.9±0.02 vs 0.5±0.04, p&lt;0.01, n=2/group). While the SSWG rat are protected from the development of maternal syndrome compared to the SSC, the exact mechanisms for this protection is unknown. This study demonstrates how environmental factors such as diet can play a protective role in the development of maternal syndrome with associated effects on the health of the offspring.Support or Funding InformationHL116264, 18POST33990140, 15SFRN2391002This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Use of intravoxel incoherent motion MR imaging to assess placental perfusion in patients with placental adhesion disorder on their third trimester

ObjectiveOur primary aim was to investigate if women with placenta accreta can be differentiated with women without using IVIM quantitative assessment of the placental perfusion. A second aim was to investigate if IVIM parameters could be used to differentiate placenta accreta from increta. MethodsThe study population included 17 patients with placenta accreta, 29 patients with placenta increta and 16 patients without placenta accreta between 28 + 0 to 41 + 6 weeks. All women underwent a MRI examination including an IVIM sequence at 1.5 T. The perfusion fraction (f), pseudodiffusion coefficient (D*) and standard diffusion coefficient (D) were calculated. Results Women with placenta accreta and increta had a smaller placenta perfusion fraction (P < 0.05) than patients without placenta accreta, placental perfusion fraction didn't differ between placenta accreta and increta (p > 0.05). Differences of D and D* in three groups showed no statistical significance (p > 0.05). ConclusionPlacenta accreta and increta differ in placental perfusion fraction from women without the disease. The perfusion fraction can be used as a feasible index to evaluate placenta perfusion.

The role of disordered angiogenesis tissue markers (sflt-1, Plgf) in present day diagnosis of preeclampsia.

Preeclampsia and conditions associated with impaired placental perfusion develop in almost 10% of all pregnancies. Patho- logic angiogenesis is one of the processes observed in preeclampsia. sFlt-1, PlGF and the sFlt-1/PlGF ratio are new and promising angiogenesis-related biomarkers. Our paper describes the present status of, and clinical practice opportunities for, these factors. According to present data, sFlt-1, PlGF and the sFlt-1/PlGF ratio are very useful tools in assessing placental angiogenesis abnormalities associated with preeclampsia and can be use in clinical practice.

Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta.

Intrahepatic cholestasis of pregnancy (ICP) causes increased transfer of maternal bile acids to the fetus and an increased incidence of sudden fetal death. Treatment includes ursodeoxycholic acid (UDCA), but it is not clear if UDCA protects the fetus. This study explores the placental transport of the bile acid taurocholate (TC) by the organic anion–transporting polypeptide, (OATP)4A1, its effects on the placental proteome and vascular function, and how these are modified by UDCA. Various methodological approaches including placental villous fragments and Xenopus laevis oocytes were used to investigate UDCA transport. Placental perfusions and myography investigated the effect of TC on vasculature. The effects of acute TC exposure on placental tissue were investigated using quantitative proteomics. UDCA inhibited OATP4A1 activity in placental villous fragments and oocytes. TC induced vasoconstriction in placental and rat vasculature, which was attenuated by UDCA. Quantitative proteomic analysis of villous fragments showed direct effects of TC on multiple placental pathways, including oxidative stress and autophagy. The effects of TC on the placental proteome and vasculature demonstrate how bile acids may cause fetal distress in ICP. UDCA inhibition of OATP4A1 suggests it will protect the mother and fetus against the vascular effects of TC by inhibiting its cellular uptake. UDCA may protect the fetus in ICP by inhibiting OATP4A1-mediated bile acid transfer and TC-induced placental vasoconstriction. Understanding the physiologic mechanisms of UDCA may allow better therapeutic interventions to be designed specifically for the fetus in the future.—Lofthouse, E. M., Torrens, C., Manousopoulou, A., Nahar, M., Cleal, J. K., O’Kelly, I. M., Sengers, B. G., Garbis, S. D., Lewis, R. M. Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta.

Expression of genes involved in inflammation and growth - does sampling site in human full-term placenta matter?

Objective To investigate the placental gene expression of substances in the inflammatory cascade and growth factors at nine different well-defined sampling sites in full-term placentas from 12 normal weight healthy non-smoking women with an uncomplicated singleton pregnancy. Methods All placentas (six girls and six boys) were delivered vaginally. Quantitative real-time polymerase chain reaction was used to analyze toll receptor-2 and -4, interleukin-6 and -8, tumor necrosis factor-α, leptin, ghrelin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor (IR). Results The leptin gene and the IR gene showed higher expression in lateral regions near the chorionic plate compared to central regions near the basal plate (P = 0.028 and P = 0.041, respectively). Conclusion Our results suggest that the sampling site may influence the gene expression for leptin and IR in placental tissue obtained from full-term normal pregnancies. We speculate that this may be due to differences in placental structure and perfusion and may be important when future studies are designed.

Efficacy of oral L-arginine on amniotic fluid index in pregnant women with oligohydramnios attending antenatal clinic in a tertiary care hospital in Telangana, India

Background: Oligohydramnios leads to feto-maternal morbidity and mortality. Though there is no specific treatment for oligohydramnios, use of L-arginine seems to be promising. As a nitric oxide donor, it causes vasodilatation, increases placental perfusion and finally increases amniotic fluid. However, data on the use of L-arginine for oligohydramnios is scarce. Hence, this study was aimed to evaluate the efficacy of oral L-arginine on Amniotic Fluid Index (AFI) and to document the pregnancy outcomes in women with oligohydramnios.Methods: This was a prospective observational study conducted on pregnant women attending antenatal clinic (ANC) at Mediciti Institute of Medical Sciences (MIMS), Ghanpur, Telangana, India from 1st January 2018 to 30th June 2018.Results: A total of 50 participants were enrolled and 4 participants among them were lost to follow- up. Mean age (SD) of the women enrolled was 23.3 (3.49) years. Mean gestational age (SD) at the time of diagnosis was 34.61 (1.53) weeks. Mean AFI (SD) at the time of diagnosis and after treatment with L-arginine were 6.8 (1.3) cm and 9.4 (2.82) cm respectively. After a mean treatment duration (SD) of 3.23 (1.38) weeks, a mean (SD) increase of AFI by 2.6 (1.57) cm (P &lt;0.0001) was observed. An increase of AFI was noted in 84.78% of cases (P &lt;0.0001). Mean (SD) Gestational age at the time of delivery was 38.25 (1.48) weeks. Only 37% of participants required operational deliveries. Mean (SD) birth weight of the new borns was 2.54 (0.47) kg. Neonatal Intensive Care Unit (NICU) admissions were required in 32.6% of new borns.Conclusions: L-arginine is efficacious in improving AFI in oligohydramnios. AFI improvement could possibly lead to better neonatal outcomes by reducing preterm deliveries and operative interventions.

Limited AT1 Receptor Internalization Is a Novel Mechanism Underlying Sustained Vasoconstriction Induced by AT1 Receptor Autoantibody From Preeclampsia.

BackgroundAngiotensin II type 1 receptor (AT 1R) autoantibody (AT1‐AA) was first identified as a causative factor in preeclampsia. Unlike physiological ligand angiotensin II (Ang II), AT1‐AA can induce vasoconstriction in a sustained manner, causing a series of adverse effects, such as vascular injury and poor placental perfusion. However, its underlying mechanisms remain unclear. Here, from the perspective of AT 1R internalization, the present study investigated the molecular mechanism of sustained vasoconstriction induced by AT 1R autoantibody.Methods and ResultsIn the current study, we used the vascular‐ring technique to determine that AT1‐AA‐positive IgG, which was obtained from the sera of preeclamptic patients, induced long‐term vasoconstriction in endothelium‐intact or endothelium‐denuded rat thoracic arteries. The effect was caused by prolonged activation of AT 1R downstream signals in vascular smooth muscle cells, including Ca2+, protein kinase C, and extracellular signal‐regulated kinase 1 and 2. Then, using subcellular protein fractionation, cell surface protein biotinylation, and total internal reflection fluorescence, we found that AT1‐AA‐positive IgG resulted in significantly less AT 1R internalization than in the Ang II treatment group. Moreover, through use of fluorescent tracing and bioluminescence resonance energy transfer, we found that AT1‐AA‐positive IgG cannot induce the recruitment of β‐arrestin1/2, which mediated receptor internalization. Then, the effect of sustained AT 1R activation induced by AT1‐AA‐positive IgG was rescued by overexpression of β‐arrestin2.ConclusionsThese data suggested that limited AT 1R internalization resulting from the inhibition of β‐arrestin1/2 recruitment played an important role in sustained vasoconstriction induced by AT1‐AA‐positive IgG, which may set the stage for avoiding AT 1R overactivation in the management of preeclampsia.