Imbalance Of Angiogenic Factors Research Articles

Soluble endoglin as a diagnosis glycoprotein in preeclampsia

Background: Angiogenic factor imbalance, such as that caused by soluble endoglin (sEng), is a feature of preeclampsia. However, the connection between sEng and clinical and laboratory indicators, and the severity of preeclampsia is not entirely understood.Methods: Ninety subjects were incorporated in this study, 30 were healthy pregnant with mean age (35.6) years. (32) mild Preeclampsia case with mean age (32.65) years preeclampsia, and (30) sever PE with mean age (32.65) wherever all women were more than 24 weeks of pregnancy. Mean blood pressure and level of proteinuria were used as indicators of the severity of the disease. ELISA was used to measure the levels of sEng in the serum. Serum lipid profile was measured by enzymatic methods. The qualitative dip-stick technique (CYBOWTM DFI Co Ltd, Republic of Korea) was used to assess the amount of urine protein.Results : A substantial difference between the PE group's serum sEng concentration and that of the healthy subjects (p 0.001) could be seen. Serum sEng concentrations of patients with moderate PE and those with severe PE differed significantly. Additionally, there were strong positive relationships between the serum sEng concentration and the SBP and proteinuria. serum sEng levels, biochemical indicators, and other factors, however, did not significantly correlate. The diagnostic accuracy (86.2) in distinguishing mild PE from the healthy patient group was good thanks to the excellent area under the curve (AUC = 0.827, p < 0.0001). Conclusion: Levels of sEng in sera of PE patients were elevated. sEng was significantly correlated with PE patients.Keywords: Soluble Endoglin; Preeclampsia; Proteinuria; Blood Pressure

A Case of Partial Molar Pregnancy Complicated by HELLP and PRES

Introduction: The term gestational trophoblastic disease encompasses premalignant and malignant conditions arising from trophoblastic cells. Premalignant disorders include complete or partial hydatidiform mole, whereas malignant disorders include invasive mole, choriocarcinoma, and placental-site trophoblastic tumor. Partial hydatidiform moles are triploid in nature and occur when 2 sperm fertilize a single ovum. Preeclampsia is a syndrome complicating 2-8% of pregnancies which presents as new-onset hypertension plus proteinuria. The occurrence of hemolysis, elevated liver enzymes and low platelet count, referred to as HELLP syndrome, is a severe form of preeclampsia. A related severe manifestation is posterior reversible encephalopathy syndrome (PRES) - a clinicoradiological syndrome characterized by symptoms including headache, seizures, altered consciousness and visual disturbances. PRES is commonly associated with acute hypertension. The symptoms of PRES vary widely: i.e., the visual disturbance can vary from blurred vision and homonymous hemianopsia to cortical blindness. Seizures and status epilepticus are common. Although preeclampsia and HELLP syndrome rarely occur before 20-weeks of gestation, reports have suggested early occurrences of these hypertensive disorders specifically in the setting of a molar pregnancy. Case Report: The patient is a 23-year-old, female gravida 1 at 16 week 5 days who presented to an outside emergency department with a 3-day history of progressive abdominal pain which radiated to her back, arms, and shoulders. At the outside facility, the patient had multiple systolic blood pressures greater than 160 mmHg and had a witnessed 30-second seizure which resolved with an intravenous (IV) injection of 2-mg of Lorazepam and 4-gram magnesium sulfate loading dose. She was initiated on magnesium sulfate maintenance pending transfer to our institution. On admission, the patient met criteria for eclampsia and HELLP (platelets 79,000 K/uL, AST 144 U/L, ALT 96 U/L, LDH 482 U/L, Hemoglobin 8.7 g/dL). The beta human chorionic gonadotropin level (HCG) was greater than 200,000 mIU/mL. Bedside ultrasound suggested the presence of an enlarged cystic placenta and a growth restricted fetus (estimated fetal weight 124g, 2%). The patient and her family were counseled and the decision was made to proceed with misoprostol induction and termination of the pregnancy due to maternal indications. During the induction, the patient developed significant vaginal bleeding and was taken to the operating room for an uncomplicated dilation and evacuation. After the procedure, the patient developed progressive visual blurring with 4+ hyperreflexia. Magnetic resonance imaging (MRI) of the brain with and without contrast was obtained with findings significant for PRES. The MRI revealed T2 high-signal lesions within the cortex of the bilateral occipital lobes. Neurology was consulted and recommended blood pressure control and initiation of levetiracetam for seizure prophylaxis. She was initiated on long-acting nifedipine with subsequent blood pressure control. Patient’s visual symptoms and hyperreflexia resolved. Her liver function tests, platelets, and LDH also returned to normal. The patient received contraceptive counseling to prevent pregnancy during gestational neoplastic disease surveillance period. She underwent weekly beta-hCG until negative, followed by three weekly consecutive negative levels before spacing measurements to every 3 months for a period of six months per National Comprehensive Cancer Network (NCCN) guidelines. The pathology results indicated the presence of chorionic villi composed of both large hydropic and smaller normal-appearing villi, a 69.3-gram female fetus compatible with caudal neurocutaneous defect with abnormal localization of brain tissue. The genetic profile of the villous tissue consisted of two sets of dispermic paternal alleles in addition to one set of maternal alleles consistent with a partial mole diagnosis. Discussion: There is an association between preeclampsia and molar pregnancy. Of partial hydatidiform molar pregnancies, 41.9% will develop the symptoms of preeclampsia if left untreated. Although the pathophysiology of eclampsia spectrum disorders is incompletely understood, some evidence points to the role of increased death of trophoblasts and the maternal inflammatory response to trophoblast deportation. Additional evidence points to angiogenic factor imbalance and interestingly, molar placentas produce high levels of antiangiogenic factors. Other causative agents include placental factors that trigger maternal endothelial activation. It is known that trophoblastic debris shed from the placenta into the maternal blood is associated with this condition. It has been demonstrated that trophoblastic debris from molar pregnancies also induces endothelial cell activation through heat-shock protein 70 (HSP70) expressed on a hydatidiform molar placenta, which may be a pathogenic signal to endothelial cells. This case reiterates the association between hydatidiform moles and the hypertensive disorders of pregnancy possibly supporting the theories that such disorders may share an etiologic linkage through trophoblast debris and angiogenic factor imbalance. This case also supports screening molar pregnancies for severe preeclampsia syndrome.

Irregularities of Coagulation in Hypertension.

This review article summarizes the role of coagulation in the pathogenesis of hypertension. It specifically focuses on significant factors and markers associated with coagulation, including D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, β-thromboglobulin, and Stuart-Prower factor. D-dimer levels were elevated in hypertensive individuals compared to healthy controls, and the levels increased with the severity of hypertension. These findings indicate that increased coagulation activity of fibrin plays a role in the development of thromboembolic complications in hypertensive patients. Additionally, both fibrinogen levels and D-dimer levels displayed a positive correlation with the duration of hypertension, suggesting that these biomarkers were positively associated with the length of time an individual had been hypertensive. Increased systolic and diastolic blood pressures have been linked to higher levels of prothrombin time and activated partial thromboplastin time in individuals with hypertension as well as those with normal blood pressure. Also, the presence of P-selectin, produced by activated platelets and endothelial cells during angiotensin II stimulation, played a role in the development of cardiac inflammation and fibrosis associated with hypertension. Moreover, the change in systolic blood pressure was associated with baseline soluble urokinase plasminogen activator receptor (suPAR) in hypertensive participants, and the change in suPAR levels was associated with the development of hypertension. Moreover, it was observed a decrease in thrombomodulin expression in the placenta of preeclamptic patients, suggesting its potential involvement in placental dysfunction, possibly driven by an imbalance in angiogenic factors. Tissue factors and autophagy might have significant implications in the pathogenesis of chronic thromboembolic pulmonary hypertension, particularly in the context of vascular remodelling. Likewise, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) might be a promising biomarker for the early detection of pulmonary arterial hypertension and the von Willebrand factor is a candidate prognostic biomarker. The arterial β-thromboglobulin levels were significantly lower than venous levels. This article concludes that D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, and β-thromboglobulin are important factors involved in the pathogenesis of hypertension.

Aspirin and Pravastatin for Preeclampsia Prevention in High-Risk Pregnancy

Preeclampsia is a hypertensive disorder of pregnancy affecting up to 8% of pregnancies. It is associated with significant neonatal and maternal morbidities and mortality. Although its pathogenesis is not completely understood, abnormal placentation resulting in imbalance in angiogenic factors, increased inflammation, and endothelial dysfunction are thought to be key pathways in the development of the disease. Administration of low-dose aspirin is recommended by professional societies for the prevention of preeclampsia in high-risk individuals. In this review, we summarize the evidence behind the use of low-dose aspirin and pravastatin in pregnant individuals at high risk of preeclampsia.

Glucose degradation products in peritoneal dialysis solution impair angiogenesis by dysregulating angiogenetic factors in endothelial and vascular smooth muscle cells.

The accumulation of glucose degradation products (GDPs) during peritoneal dialysis (PD) can lead to immature angiogenesis in the peritoneum. However, the effect of GDPs on angiogenesis, at concentrations observed in dialysate effluent, has not been widely investigated. We do not know how the inflammation observed in PD-related peritonitis affects angiogenesis of the peritoneum. Human umbilical vessel endothelial cells (HUVEC) and human umbilical aortic smooth muscle cells (HUASMC) were used to examine the response to the three main GDPs found in peritoneal dialysate (methylglyoxal (MGO), 3-deoxyglucosone (3-DG), and 5-hydroxymethylfurfural (5-HMF). Supernatant from lipopolysaccharide (LPS)-activated murine macrophage cell lines (RAW 264.7 cells) were used to stimulate angiogenesis in the peritoneum. Changes in the expression of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor B (PDGFB) in HUVEC, and PDGF-receptor beta (PDGF-Rβ) in HUASMC, were examined by real-time PCR, Western blot, and ELISA. In HUVECs, the expression of PDGFB mRNA and protein were decreased by exposure to MGO, 3-DG, and 5-HMF at concentrations observed in dialysate effluent. A subsequent decrease in secreted PDGF-BB was observed. In HUASMCs, MGO and 5-HMF increased the expression of VEGF-A mRNA and protein, while 5-HMF decreased the expression of PDGF-Rβ. VEGF-A is upregulated, and PDGF-Rβ is downregulated, by conditioned medium of LPS-stimulated macrophages in HUASMCs. The GDPs of PD effluent cause an imbalance of angiogenic factors in endothelial cells and vascular smooth muscle cells that may lead to immature angiogenesis in the peritoneum.

Angiogenic biomarkers for the follow-up of singleton pregnancies with suspected preeclampsia.

Preeclampsia (PE) is a hypertensive disorder of pregnancy and one of the leading causes of maternal and fetal morbidity and mortality worldwide. While the underlying cause of remains unknown, abnormal placentation in early stages of pregnancy is thought to be a main triggering event for the more severe and early-onset forms. A consequence of placental insufficiency is an imbalance of angiogenic factors in the maternal circulation. The objective was to assess the utility of the angiogenic biomarker sFlt-1/PlGF for the diagnosis, follow-up and prognosis of preeclampsia. This was a retrospective cohort study based including 65 consecutive singleton pregnancies with suspected preeclampsia referred to our hospital between January 2018 and February 2019. PE was defined as early-onset (20-33+6 weeks) and late-onset (≥34 weeks). The main independent variable was sFlt-1/PlGF classified in women with early or late onset PE, respectively, as low when <38 or <38, intermediate when 38-84 or 38-109, and high when ≥85 or ≥110. PE was confirmed in 14 (4 early-onset, 10 late-onset) of the participants. 122 sFlt-1/PIGF ratio determinations were requested. The optimal sFlt-1/PlGF to predict PE was ≥86 with a sensitivity of 93% and a specificity of 96% (AUC 0.95; CI 95% 0.90-1.0; P<0.001). A multilevel logistic model for the diagnosis of PE was adjusted for age, Body Mass Index, diabetes, proteinuria and mean arterial pressure. Women were 16.5 times (P=0.013) more likely to develop PE if they had intermediate sFlt-1/PlGF levels and 451 times (P<0.001) more likely if they had high biomarker levels compared to those with levels below 38. The probability of PE was 3.73 times (P=0.046) greater in those with maternal and/or fetal complications. The biomarker proved useful to diagnose PE and assess its prognosis. Patients diagnosed with PE had a higher frequency of complications and their newborns were of lower birth weight.

Mesenchymal stem cell therapy attenuates complement C3 deposition and improves the delicate equilibrium between angiogenic and anti-angiogenic factors in abortion-prone mice

Immunological disorders are one of the main causes of recurrent spontaneous abortions (RSA). A rapidly expanding body of evidence indicates that excessive activation of the complement system is critically involved in the development of miscarriages. In the CBA/J × DBA/2 murine model of recurrent miscarriage, exaggerated and unrestrained complement activation is reported to be the underlying cause of angiogenic factor imbalance and persistent inflammation. We have previously shown that mesenchymal stem cell (MSC) therapy can significantly reduce the abortion rate in abortion-prone mice through regulating the feto-maternal immune response. In the present study, we hypothesized that MSCs might improve the balance of angiogenic factors at the feto-maternal unit of CBA/J × DBA/2 mice by restraining complement activation and deposition.To explore this hypothesis, autologous adipose tissue-derived mesenchymal stem cells (AD-MSCs) were administered intra-peritoneally to abortion-prone mice on the 4.5th day of gestation. Control mice received PBS as vehicle. On day 13.5 of pregnancy, deposition of the complement component C3 and expression levels of Crry, CFD (adipsin), VEGF, PlGF and FLT-1 were measured at the feto-maternal interface by immunohistochemistry and real-time PCR, respectively. Decidual cells were also cultured in RPMI 1640 medium for 48 h and VEGF and sFLT-1 protein levels were quantified in supernatants using enzyme-linked immunosorbent assay (ELISA).Our results indicated that MSC therapy significantly reduced C3 deposition and adipsin transcription in the fetal-maternal interface of abortion-prone mice. Furthermore, administration of MSCs robustly upregulated the mRNA expression levels of Crry, VEGF, PlGF and FLT-1 in the placenta and decidua of CBA/J × DBA/2 mice. Consistently, the in vitro results demonstrated that decidual cells obtained from MSC-treated dams produced increased concentrations of VEGF in culture supernatants, with concomitant decreased levels of sFLT-1 protein.Here, we show for the first time that adoptive transfer of MSCs rectifies the disturbed balance of angiogenic factors observed at the feto-maternal unit of CBA/J × DBA/2 mice, in part at least, through inhibiting excessive complement activation and promoting the production of angiogenic factors. Collectively, these alterations seem to play a pivotal role in reducing the abortion rate and improving the intrauterine condition for the benefit of the fetus.

Circulating angiogenic factors and HIV among pregnant women in Zambia: a nested case\u2013control study

BackgroundMaternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway.MethodsIn a case–control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth).ResultsCompared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens.ConclusionsWe present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes.

Evolution of Angiogenic Factors in Pregnant Patients with Breast Cancer Treated with Chemotherapy

Simple SummaryAnthracyclines and taxanes are being used as a standard treatment for breast cancer diagnosed during pregnancy. These chemotherapy regimens allow the continuation of pregnancy without delaying cancer treatment with relatively good maternal and neonatal outcomes. However, their effects on placental function and fetal development are not completely understood. Maternal serum angiogenic factors are a surrogate of placental function and are abnormal weeks before placental complications such as preeclampsia or intrauterine growth restriction development. In our cohort, pregnant women with breast cancer treated with chemotherapy during pregnancy show an antiangiogenic state with significantly higher levels of soluble fms-like tyrosine kinase (sFlt-1), sFlt-1/PGF ratio, and soluble endoglin (sEng) at the end of the third trimester. Angiogenic factors could be useful in the clinical obstetric management of these patients, although more studies are guaranteed.High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during pregnancy (PBC-CHT). Aim: To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for placental insufficiency, that could explain perinatal outcomes. Methods: Prospective study between 2012 and 2016 in a single institution. Soluble fms-like tyrosine kinase (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) in maternal blood were assessed throughout pregnancy in 12 women with BC and 215 controls. Results: Cancer patients were treated with doxorubicin-based regimes and with taxanes. Ten PBC-CHT (83%) developed obstetrical complications. At the end of the third trimester, significantly higher levels of sFlt-1; sFlt-1/PGF ratio, and sEng levels were observed in BC women as compared to controls. Moreover; there was a significant correlation between plasma levels of sFlt-1 and the number of chemotherapy cycles administered. Besides, more chemotherapy cycles correlated with lower birthweight and head circumference at birth. Conclusions: Women with BC treated during pregnancy showed an antiangiogenic state compatible with placental insufficiency. Angiogenic factors could be useful in the clinical obstetric management of these patients; although further studies will be required to guide clinical decision-making.

Role Of Soluble Endoglin In The Diagnosis Of Preeclampsia Severity In Iraqi Women

Background: Preeclampsia is a multiorgan disorder and characterized by an imbalance in angiogenic factors, including soluble endoglin (sEng). Till now, the relationship between serum levels of sEng with the severity of preeclampsia is not fully elucidated. The study aimed to clarify the precision of serum soluble endoglin (sEng) in the diagnosis of preeclampsia. Materials and Methods: A case–control study has been conducted in the Department of Obstetrics and Gynaecology and clinical biochemistry department, Al-Yarmouk Teaching Hospital, college of medicine/ Mustansiriyah university, Baghdad-Iraq for six months duration. A total of 130 subjects were enrolled. Among them, 40 subjects of non-severe preeclampsia patients (Group 1), 40 of severe preeclampsia (Group 2), and 50 healthy pregnant normotensive women served as controls. Levels were estimated by enzyme-linked immunosorbent assay technique (ELISA) in both cases and controls. Results: There are no significant differences in age among the three groups with a mean age of controls (27.62 ± 4.76), non-severe PE (27.72 ± 5.99), and severe PE (27.90 ± 5.34) years with (p > 0.05). Similarly, no significant differences between non-severe PE and severe PE groups regarding gestational age when compared to the control group (p < 0.691). Mean level of sEng was the highest in severe preeclampsia group (4.04 ± 2.60 ng/mL) as compared to non-severe group (1.63 ± 0.41) and in controls (0.11 ± 0.28) with p-value (p< 0.001). The results showed that the area-under-the-curve (AUC) of serum soluble Endoglin in cases compared with control was (1.00) with a confidence interval (95% CI). The sensitivity and specificity for sEng in PE groups were (100%). On the other hand, compared with the control group, PE groups showed significantly higher creatinine, blood urea, uric acid, ALT, and AST (p < 0.001). Platelet, hemoglobin, PCV, PT, and PTT showed a significant decrease when compared to control at p-value (p = < 0.001) for the first three, (p = 0.001) for PT and low significant for the last (p = 0.03). sEng levels were moderately correlated with platelets (r = 0.312), (p

Increasing efficiency of preterm birth prediction

Abstract. The disturbed placentation in a certain way plays an important role in the pathogenesis of great obstetric syndromes. Therefore, the possibility of using biochemical indicators of the level of placental growth factor (PlGF) and fms-like tyrosine kinase (sFlt-1) for predicting preterm labor is of great interest. The aim of the study was developing criteria for predicting preterm labor based on the combined use of ultrasound cervicometry and the concentration of PlGF and sFlt-1. Materials and methods. A total of 227 pregnant women were examined, 190 of whom had preterm birth. Group I included 48 women whose pregnancy completed at 23 to 27 weeks. In group II, 142 women with prematurity in terms of 28 to 36 weeks were observed. Group III included 37 women with a healthy pregnancy, which completed at 38–41 weeks. All patients involved in the study underwent ultrasound cervicometry on a Voluson 730 (GE Healthcare, USA) at 16 weeks, and also the concentration of PlGF and sFlt-1 in blood serum by electrochemiluminescence immunoassay using a Cobas e411 analyzer was studied (Roche diagnostics, Switzerland). Results. The study revealed a significant (p &lt; 0.001) decrease in the average concentration of PlGF in the blood serum by 65 % associated with an increased level of sFlt-1 by 93% in women with early termination of pregnancy – 23–27 weeks (group I) in relation to women with a healthy pregnancy. In women with preterm birth at 28–36 weeks of gestation (group II), a similar trend of changes was observed: the PlGF level significantly (p = 0.014) decreased on average by 68 % in relation to women with a healthy pregnancy. In women of group I, the value of the sFlt-1 / PlGF ratio exceeded (p &lt; 0.001) the values of patients in group III by 14 times. But an even more pronounced imbalance of angiogenic factors was observed in women of group II – on average 16 times. Two main markers were used to predict premature birth: shortening of the cervix according to ultrasound cervicometry data of less than 30 mm, as well as the sFlt-1/PlGF ratio of more than 50 conv. units. The odds ratio (OR) of preterm birth in the case of using only the length of the cervix was 34,133 (95 % confidence interval – 12.308–94.660). OR in the case of combined use of cervicometry data and angiogenesis variables was 148.750 (95 % confidence interval – 33.243–665.593). Conclusion. Thus, the use of an additional biochemical marker significantly improved the accuracy of preterm labor prediction.

Circulating angiogenic factors are associated with progression to preeclampsia and the occurrence of adverse outcomes in women with gestational hypertension.

Gestational hypertension is characterized by an imbalance in angiogenic factors. The goal of the current study was to evaluate whether circulating concentrations of proangiogenic and antiangiogenic factors are associated with the risk of progression to preeclampsia and development of adverse outcomes in women with gestational hypertension. We studied 496 women with gestational hypertension. Patients were divided into three groups based on their degree of angiogenic imbalance, evaluated by the soluble fms-like tyrosine kinase-1/placental growth factor ratio: no angiogenic imbalance (≤38), mild angiogenic imbalance (>38-<85), and severe angiogenic imbalance (≥85) or stratified into tertiles according to soluble endoglin (sEng) levels. The concentrations of all angiogenic factors were significantly different in patients with gestational hypertension than in healthy pregnancy. A significant trend towards higher serum sEng levels was observed as the degree of angiogenic imbalance increased. Patients with severe angiogenic imbalance had higher rates of adverse maternal and perinatal outcomes and progression to preeclampsia (P < 0.001) when compared with patients with no or mild angiogenic imbalance. The risk of combined adverse maternal outcomes and specific adverse outcomes (hemolysis, elevated liver enzymes, low platelet count syndrome, preterm delivery, small-for-gestational-age infant, perinatal death, and progression to preeclampsia within 7, 14, 28, and 56 days) was higher in patients with severe angiogenic imbalance or sEng values in the highest tertile (odds ratio ≥5.6 and ≥2.0, respectively), compared with no angiogenic imbalance or the lowest tertile. In women with gestational hypertension at the time of initial evaluation, circulating concentrations of the soluble fms-like tyrosine kinase-1/placental growth factor ratio and sEng appear to be suitable markers to assess the risk of adverse maternal and perinatal outcomes and progression to preeclampsia.

Preeclampsia for the Nephrologist: Current Understanding in Diagnosis, Management, and Long-term Outcomes.

Preeclampsia is a multisystem progressive disorder of pregnancy that can be potentially catastrophic for the mother and the fetus. It involves complex perturbations of the kidney and systemic physiology, along with long-term effects on vascular and kidney health. Thus, the nephrologist plays a key role in the peripartum and long-term management of preeclampsia. Recent translational research has improved our understanding of its pathophysiology, and there is hope for novel therapies. In this review, we discuss the evolution of diagnostic criteria and dilemmas in the diagnosis of hypertensive disorders in pregnancy. We summarize the advances in the pathogenesis and prediction of preeclampsia. We describe the management and prevention of preeclampsia focusing specially on the forthcoming strategies from the nephrologist's perspective. We address the evidence regarding long-term outcomes for the mother and the child. We end with exploring areas warranting future research.

Preeclampsia and Kidney Disease: Deciphering Cause and Effect.

Preeclampsia and chronic kidney disease have a complex, bidirectional relationship. Women with kidney disease, with even mild reductions in glomerular filtrate rate, have an increased risk of developing preeclampsia. Preeclampsia, in turn, has been implicated in the subsequent development of albuminuria, chronic kidney disease, and end-stage kidney disease. We will discuss observational evidence and mechanisms linking the two disease processes. Preeclampsia is characterized by an imbalance in angiogenic factors that causes systemic endothelial dysfunction. Chronic kidney disease may predispose to the development of preeclampsia due to comorbid conditions, such as hypertension, but is also associated with impaired glycocalyx integrity and alterations in the complement and renin-angiotensin-aldosterone systems. Preeclampsia may lead to kidney disease by causing acute kidney injury, endothelial damage, and podocyte loss. Preeclampsia may be an important sex-specific risk factor for chronic kidney disease. Understanding how chronic kidney disease increases the risk of preeclampsia from a mechanistic standpoint may open the door to future biomarkers and therapeutics for all women.

Transcription factor AP2A affects sFLT1 expression and decidualization in decidual stromal cells: Implications to preeclampsia pathology

Preeclampsia (PE) yields a spectrum of phenotypic expression, leading to varying degrees of hypertension, maternal renal dysfunction and placental insufficiency with resultant maternal and neonatal morbidity. Increased sFLT1 expression contributing to angiogenic factor imbalance, placental hypoxia, failed immune adaptation to the fetus and defective decidualization are among the commonly proposed theories of PE pathogenesis. Recently researchers have focused their attention on the events that occur at the maternal fetal interface as potential contributors to PE pathogenesis. Decidual stromal cells (DSC) isolated from preeclamptic women show diminished ability to decidualize upon stimulation and reduced capacity to downregulate sFlt-1 levels. In this study, we sought to gain insight into the molecular mechanism(s) involved in the aberrant decidualization capacity of PE DSC. Our findings using qRT-PCR show that PE DSCs have 6-fold higher basal levels of transcription factor AP2A (TFAP2A) RNA compared to women without PE and that expression of TFAP2A increases during decidualization but only in DSCs of normotensive (NT) women. Silencing of TFAP2A using Trilencer siRNA upregulated sFLT1 expression only in NT-DSCs but suppressed the expression of decidualization markers PRL, IGFBP1 and their regulator FOXO1 in cells from both groups. Collectively, our observations suggest that TFAP2A acts as a repressor of sFLT1 and plays a necessary role in decidualization possibly through interacting with another factor that is aberrantly expressed in PE DSCs.

Soluble Endoglin As a Marker for Preeclampsia, Its Severity, and the Occurrence of Adverse Outcomes.

Preeclampsia is characterized by an imbalance in angiogenic factors, including sEng (soluble endoglin). However, the relationship of sEng with the severity of preeclampsia, clinical, and laboratory parameters, and the occurrence of adverse outcomes are not fully elucidated. We studied 1002 women with preeclampsia. Serum concentrations of sEng were measured by ELISA. Serum sEng levels were significantly different (P<0.001) in patients with preeclampsia than in healthy pregnancy. In addition, these factors were markedly different in patients with hemolysis, elevated liver enzymes, low platelet count syndrome and eclampsia than in patients with preeclampsia with or without severe features (P<0.001) and in patients with preeclampsia with severe features than in those without severe features (P<0.001). sEng correlated positively with blood pressure, proteinuria, and levels of creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase; and inversely with gestational age, infant's birth weight, and platelets counts (P<0.001 for all). The risk of combined and specific adverse outcomes (pulmonary edema, acute renal failure, placental abruption, hepatic hematoma or rupture, maternal death, cerebral hemorrhage, thrombocytopenia, elevated liver enzymes, preterm delivery, small for gestational age infant, and need for endotracheal intubation, positive inotropic drug support, and hemodialysis) was higher in patients with sEng values in the highest quartile (odds ratio ≥3.1) compared with the lowest quartile. Patients in the highest quartile of sEng were more likely to deliver early compared with those in the lowest quartile (HR, 2.33; 95% CI, 1.91-2.84). We concluded that circulating concentrations of sEng seem to be a suitable marker to assess the severity of preeclampsia and are associated with increased risk of adverse outcomes.

Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice.

Preeclampsia remains a clinical challenge due to its poorly understood pathogenesis. A prevailing notion is that increased placental production of soluble fms-like tyrosine kinase-1 (sFlt-1) causes the maternal syndrome by inhibiting proangiogenic placental growth factor (PlGF) and VEGF. However, the significance of PlGF suppression in preeclampsia is uncertain. To test whether preeclampsia results from the imbalance of angiogenic factors reflected by an abnormal sFlt-1/PlGF ratio, we studied PlGF KO (Pgf-/-) mice and noted that the mice did not develop signs or sequelae of preeclampsia despite a marked elevation in circulating sFLT-1. Notably, PlGF KO mice had morphologically distinct placentas, showing an accumulation of junctional zone glycogen. We next considered the role of placental PlGF in an established model of preeclampsia (pregnant catechol-O-methyltransferase-deficient [COMT-deficient] mice) by generating mice with deletions in both the Pgf and Comt genes. Deletion of placental PlGF in the context of COMT loss resulted in a reduction in maternal blood pressure and increased placental glycogen, indicating that loss of PlGF might be protective against the development of preeclampsia. These results identify a role for PlGF in placental development and support a complex model for the pathogenesis of preeclampsia beyond an angiogenic factor imbalance.

77. The role of VEGF as prognostic marker of Preeclampsia

Background Preeclampsia is one of the most frequent and severe pregnancy complications, which reaches 15–25% women in our country. It was found that the formation of hypertensive states in pregnancy due to endothelial dysfunction and the associated imbalance of angiogenic factors. The danger lies in the development of complications such as preeclampsia or eclampsia, fetoplacental insufficiency, fetal growth retardation, fetal hypoxia and fetal death. The aim of the work was to study role of VEGF as prognostic marker of preeclampsia. Methods We studied 84 pregnant women in different weeks of gestation, with various type of preeclampsia and 40 healthy pregnant women, which was the control group. All pregnant women were treated in Tashkent Maternal Complex ‘-6. All women underwent standard lab tests according to modern protocols. We investigated vascular endothelial growth factor (VEGF) determined by enzyme immunoassay. Results In control group the level of VEGF has averaged 5,4 ± 0,3 pg/ml. In women with preeclampsia in II trimester 11,6 ± 0,6 pg/ml, III trimester 22,2 ± 1,4 pg/ml. Emphasis is placed on the following most significant changes in the content of VEGF in serum. Two times increasing in VEGF in the serum of women with preeclampsia. During pregnancy level of VEGF in II and III trimester increasing remains stable. The level of VEGF in physiological pregnancy is increasing only in the first 10 weeks. In the subsequent curve, reflecting the content of VEGF accepts plateau-like character and does not change until the end of pregnancy. Conclusions Increased production of growth factor is nonspecific and is likely to reflect the disturbance of angio-and vasculogenesis. Increased VEGF is already in I trimester of pregnancy can be understood as an early sign of predicting the formation of obstetric pathology at a later stage of pregnancy. Increased level of VEGF in the II and III trimester could be a predicted factor of preeclampsia.

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.

Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality. Although the etiology is unknown, PE is thought to be caused by defective implantation and decidualization in pregnancy. Pregnant blood pressure high (BPH)/5 mice spontaneously develop placentopathies and maternal features of human PE. We hypothesized that BPH/5 implantation sites have transcriptomic alterations. Next-generation RNA sequencing of implantation sites at peak decidualization, embryonic day (E)7.5, revealed complement gene up-regulation in BPH/5 vs. controls. In BPH/5, expression of complement factor 3 was increased around the decidual vasculature of E7.5 implantation sites and in the trophoblast giant cell layer of E10.5 placentae. Altered expression of VEGF pathway genes in E5.5 BPH/5 implantation sites preceded complement dysregulation, which correlated with abnormal vasculature and increased placental growth factor mRNA and VEGF164 expression at E7.5. By E10.5, proangiogenic genes were down-regulated, whereas antiangiogenic sFlt-1 was up-regulated in BPH/5 placentae. We found that early local misexpression of VEGF genes and abnormal decidual vasculature preceded sFlt-1 overexpression and increased complement deposition in BPH/5 placentae. Our findings suggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant trophoblast invasion and poor placentation that underlie PE.-Sones, J. L., Merriam, A. A., Seffens, A., Brown-Grant, D.-A., Butler, S. D., Zhao, A. M., Xu, X., Shawber, C. J., Grenier, J. K., Douglas, N. C. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.

Infantile hemangioma: pathogenesis and mechanisms of action of propranolol.

Infantile hemangioma (IH) is the most common benign tumor of childhood, with a prevalence of 4 % to 10 %. It is characterized by a proliferative rapid growth phase, which starts after a few weeks of life, followed by a slow regression phase. In IH cases that are potentially disfiguring or life-threatening (10% to 15% of all cases), systemic therapy should be promptly initiated. Data source The present study reviews published scientific articles available in reliable electronic databases. Selected were all studies that evaluated the pathogenesis of IH and the mechanisms of action of propranolol. Conclusions The pathogenesis of IH has not been fully elucidated. Studies show that, in the proliferative phase of IH, there is an imbalance of angiogenic factors and an increase in the levels of vascular endothelial growth factor and matrix metalloproteinases 2 and 9. In the regression phase, the levels of these factors decrease, whereas those of antiangiogenic factors, including tissue inhibitors of matrix metalloproteinases, increase. Since 2008, propranolol has become the drug of choice in the treatment of IH, targeting vascular tone, angiogenesis, and apoptosis. Current insights into the pathogenesis of IH allow for the development of new therapeutic strategies.