Inverted formin 2 regulates intracellular trafficking, placentation, and pregnancy outcome

Healthy pregnancy depends on proper placentation—including proliferation, differentiation, and invasion of trophoblast cells—which, if impaired, causes placental ischemia resulting in intrauterine growth restriction and preeclampsia. Mechanisms regulating trophoblast invasion, however, are unknown. We report that reduction of Inverted formin 2 (INF2) alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of Inf2 in mice recapitulates maternal and fetal phenotypes of placental insufficiency. Inf2−/− dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. Inf2−/− fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of Inf2 increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for INF2 in trophoblast invasion—a necessary process for placentation—representing a possible future target for improving placentation and fetal outcomes.

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Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk

Nature Communications ◽

10.1038/s41467-021-23827-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xiao-Hui Wang ◽

Sha Xu ◽

Xiang-Yu Zhou ◽

Rui Zhao ◽

Yan Lin ◽

...

Keyword(s):

Spontaneous Abortion ◽

Embryo Implantation ◽

Underlying Mechanism ◽

Recurrent Spontaneous Abortion ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Iron Sulfur ◽

Succinate Dehydrogenase Complex ◽

Extravillous Trophoblasts ◽

Control Study

AbstractDysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

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Prediction of Healthy Pregnancy Outcomes in Women with Overweight and Obesity: The Role of Maternal Early-Pregnancy Metabolites

Metabolites ◽

10.3390/metabo12010013 ◽

2021 ◽

Vol 12 (1) ◽

pp. 13

Author(s):

Rama J. Wahab ◽

Vincent W. V. Jaddoe ◽

Romy Gaillard

Keyword(s):

Pregnancy Outcome ◽

Early Pregnancy ◽

Pregnancy Outcomes ◽

Gestational Hypertension ◽

Characteristic Curve ◽

Overweight And Obesity ◽

Large For Gestational Age ◽

Maternal Characteristics ◽

Healthy Pregnancy ◽

Increased Risk

Women with obesity receive intensified antenatal care due to their increased risk of pregnancy complications, even though not all of these women develop complications. We developed a model based on maternal characteristics for prediction of healthy pregnancy outcomes in women with obesity or who are overweight. We assessed whether early-pregnancy metabolites improved prediction. In a population-based cohort study among a subsample of 1180 Dutch pregnant women with obesity or who are overweight, we developed a prediction model using 32 maternal socio-demographic, lifestyle, physical and pregnancy-related characteristics. We determined early-pregnancy amino acids, nonesterifed fatty acids, phospholipids and carnitines in blood serum using liquid chromatography-tandem mass spectrometry. A healthy pregnancy outcome was the absence of fetal death, gestational hypertension, preeclampsia, gestational diabetes, caesarian section, preterm birth, large-for-gestational-age at birth, macrosomia, postpartum weight retention and offspring overweight/obesity at 5 years. Maternal age, relationship status, parity, early-pregnancy body mass index, mid-pregnancy gestational weight gain, systolic blood pressure and estimated fetal weight were selected into the model using backward selection (area under the receiver operating characteristic curve: 0.65 (95% confidence interval 0.61 to 0.68)). Early-pregnancy metabolites did not improve model performance. Thus, in women with obesity or who are overweight, maternal characteristics can moderately predict a healthy pregnancy outcome. Maternal early-pregnancy metabolites have no incremental value in the prediction of a healthy pregnancy outcome.

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Preeclampsia and the brain: neural control of cardiovascular changes during pregnancy and neurological outcomes of preeclampsia

Clinical Science ◽

10.1042/cs20160108 ◽

2016 ◽

Vol 130 (16) ◽

pp. 1417-1434 ◽

Cited By ~ 24

Author(s):

Omar C. Logue ◽

Eric M. George ◽

Gene L. Bidwell

Keyword(s):

Neural Control ◽

Gestational Hypertension ◽

Gravid Female ◽

Post Traumatic Stress ◽

Neurological Outcomes ◽

Healthy Pregnancy ◽

Fetal Birth Weight ◽

Life Threatening ◽

Baroreceptor Reflex Sensitivity ◽

Post Traumatic

Preeclampsia (PE) is a form of gestational hypertension that complicates ∼5% of pregnancies worldwide. Over 70% of the fatal cases of PE are attributed to cerebral oedema, intracranial haemorrhage and eclampsia. The aetiology of PE originates from abnormal remodelling of the maternal spiral arteries, creating an ischaemic placenta that releases factors that drive the pathophysiology. An initial neurological outcome of PE is the absence of the autonomically regulated cardiovascular adaptations to pregnancy. PE patients exhibit sympathetic overactivation, in comparison with both normotensive pregnant and hypertensive non-pregnant females. Moreover, PE diminishes baroreceptor reflex sensitivity (BRS) beyond that observed in healthy pregnancy. The absence of the cardiovascular adaptations to pregnancy, combined with sympathovagal imbalance and a blunted BRS leads to life-threatening neurological outcomes. Behaviourally, the increased incidences of maternal depression, anxiety and post-traumatic stress disorder (PTSD) in PE are correlated to low fetal birth weight, intrauterine growth restriction (IUGR) and premature birth. This review addresses these neurological consequences of PE that present in the gravid female both during and after the index pregnancy.

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Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00178.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. R1326-R1343 ◽

Cited By ~ 55

Author(s):

Frank T. Spradley ◽

Ana C. Palei ◽

Joey P. Granger

Keyword(s):

Endothelial Dysfunction ◽

Vascular Dysfunction ◽

Clinical Manifestations ◽

Migration And Invasion ◽

Metabolic Factors ◽

Maternal Circulation ◽

Soluble Factors ◽

Placental Perfusion ◽

Increased Risk ◽

Placental Ischemia

Preeclampsia (PE) is a pregnancy-specific disorder typically presenting as new-onset hypertension and proteinuria. While numerous epidemiological studies have demonstrated that obesity increases the risk of PE, the mechanisms have yet to be fully elucidated. Growing evidence from animal and human studies implicate placental ischemia in the etiology of this maternal syndrome. It is thought that placental ischemia is brought about by dysfunctional cytotrophoblast migration and invasion into the uterus and subsequent lack of spiral arteriole widening and placental perfusion. Placental ischemia/hypoxia stimulates the release of soluble placental factors into the maternal circulation where they cause endothelial dysfunction, particularly in the kidney, to elicit the clinical manifestations of PE. The most recognized of these factors are the anti-angiogenic sFlt-1 and pro-inflammatory TNF-α and AT1-AA, which promote endothelial dysfunction by reducing levels of the provasodilator nitric oxide and stimulating production of the potent vasoconstrictor endothelin-1 and reactive oxygen species. We hypothesize that obesity-related metabolic factors increase the risk for developing PE by impacting various stages in the pathogenesis of PE, namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble placental factors into the maternal circulation; and 3) maternal endothelial and vascular dysfunction. This review will summarize the current experimental evidence supporting the concept that obesity and metabolic factors like lipids, insulin, glucose, and leptin affect placental function and increase the risk for developing hypertension in pregnancy by reducing placental perfusion; enhancing placental release of soluble factors; and by increasing the sensitivity of the maternal vasculature to placental ischemia-induced soluble factors.

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Preeclampsia: From Inflammation to Immunoregulation

Clinical Medicine Insights: Blood Disorders ◽

10.1177/1179545x17752325 ◽

2018 ◽

Vol 11 ◽

pp. 1179545X1775232 ◽

Cited By ~ 37

Author(s):

Denise C Cornelius

Keyword(s):

T Cells ◽

Rat Model ◽

The United States ◽

Therapeutic Interventions ◽

Trophoblast Invasion ◽

Positive Effects ◽

Immune Balance ◽

Uterine Perfusion ◽

Immune Imbalance ◽

Placental Ischemia

Preeclampsia (PE) affects 5% to 7% of pregnant women each year worldwide, accounts for up to 18% of maternal deaths in the United States each year, and is the number 1 cause of premature births. Preeclampsia is associated with hypertension after the 20th week of gestation with or without proteinuria, in conjunction with fetal growth restriction, maternal endothelial dysfunction, and chronic immune activation. The mechanisms leading to the development of PE are unclear. However, it is thought that shallow trophoblast invasion and insufficient remodeling of uterine spiral arteries result in placental ischemia. Consequently, an immune imbalance characterized by increases in proinflammatory CD4+ T cells and cytokines along with decreases in regulatory T cells and anti-inflammatory cytokines occurs. This imbalance leads to chronic inflammation and ensuing oxidative stress, proinflammatory cytokines, and autoantibodies. Studies performed in our laboratories, using the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia, have demonstrated a role for this immune imbalance to mediate PE pathophysiology and identified potential mechanisms of immunoregulation that may be of benefit in the treatment of PE. Therefore, the purpose of this commentary is to review studies demonstrating the positive effects of immunoregulatory factors in the RUPP rat model of PE. Restoration of the immune balance in PE may be a potential strategy for the development of therapeutic interventions that could improve maternal and fetal outcomes associated with this maternal syndrome.

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Abstract MP20: Prepartum 1,3-butanediol Treatment Improves Placental Perfusion In The Preeclamptic Dahl Salt-sensitive Rat

Hypertension ◽

10.1161/hyp.76.suppl_1.mp20 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Jeanne Ishimwe ◽

Michael R Garrett ◽

Jennifer M Sasser

Keyword(s):

Resistance Index ◽

Kidney Injury ◽

Late Pregnancy ◽

Treated Group ◽

Chronic Hypertension ◽

Fetal Demise ◽

Pilot Studies ◽

Placental Perfusion ◽

And Control ◽

Placental Ischemia

Chronic hypertension increases the risk of developing superimposed preeclampsia (PE). Previous reports showed that 1,3-Butanediol (BD) lowers blood pressure (BP) in male Dahl salt-sensitive (S) rats and female congenic S.SHR(11) rats which exhibit increased kidney injury over Dahl S rats. The goal of this study was to test if attenuating hypertension before pregnancy through the placentation period via BD prevents the onset of PE. Female Dahl S rats (a spontaneous model of superimposed PE, 11-16 weeks old) were divided into two groups: BD treated (20% via drinking water) and control (ad libitum water). Animals received BD for 7 weeks, baseline BP measurements (telemetry) were taken, and both groups were then mated. On gestation day (GD) 12, treatment was stopped because pilot studies showed that treatment reduced water intake during late pregnancy. Both groups were maintained on low-salt rodent chow (Teklad 7034, 0.3% NaCl; n=8/group). At GD18 (late pregnancy), uterine artery resistance index (UARI) was measured via Doppler ultrasound, 24h urine was collected on GD19, and tissues were harvested on GD20. Mean arterial pressure was lower in the treated group at baseline (141.9 ± 4.1 vs. 165.7 ± 4.5 mmHg, p= 0.008), early (135.9 ± 3.4 vs. 168.9 ± 4.6 mmHg, p= 0.0003), mid (142.0 ± 5.2 vs. 170.8 ± 4.61, p= 0.0048) but not late pregnancy (144.9 ± 5.9 vs. 161.9 ± 4.5 mmHg, p= 0.165). Late pregnancy maternal body weight was similar between groups (299.3 ± 5.6 vs. 311.3 ±7.0 g, p=0.201). Treated dams had a lower UARI (0.71 ± 0.02 vs. 0.81 ± 0.02, p=0.008) and less fetal resorptions (1.12 ± 0.29 vs. 2.25 ± 0.41, p= 0.043). No harm to the fetus was noted as no differences in pup weight (2.20 ±0.05 vs. 2.20 ± 0.09, p= 0.994) and pup length (30.19 ±0.24 vs. 29.45 ± 0.28 cm, p=0.072) were observed. Placentas from treated dams had decreased VEGF levels via ELISA (276.2 ± 33.4 vs. 498.9 ± 16.8 pg/mL, p= 0.001), suggesting reduced placental ischemia. In this study, we observed slightly improved placental perfusion and lower fetal demise following prepartum BD treatment; however, the antihypertensive effects of BD were not sustained through late pregnancy when supplementation was stopped at mid-pregnancy.

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Decreased uterine vascularization and uterine arterial expansive remodeling with reduced matrix metalloproteinase-2 and -9 in hypertensive pregnancy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00602.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. H165-H180 ◽

Cited By ~ 3

Author(s):

Chen Lin ◽

Hong He ◽

Ning Cui ◽

Zongli Ren ◽

Minglin Zhu ◽

...

Keyword(s):

Proteolytic Enzymes ◽

Gelatin Zymography ◽

Collagen Iv ◽

Intraluminal Pressure ◽

Matrix Metalloproteinase 2 ◽

Trophoblast Invasion ◽

Related Disorder ◽

Uterine Arteries ◽

Ecm Proteins ◽

Placental Ischemia

Normal pregnancy involves extensive remodeling of uterine and spiral arteries and matrix metalloproteinases (MMPs)-mediated proteolysis of extracellular matrix (ECM). Preeclampsia is characterized by hypertension in pregnancy (HTN-Preg) and intrauterine growth restriction (IUGR) with unclear mechanisms. Initial faulty placentation and reduced uterine perfusion pressure (RUPP) could release cytoactive factors and trigger an incessant cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent and depth of uterine vascularization and the proteolytic enzymes and ECM proteins involved are unclear. We hypothesized that HTN-Preg involves decreased uterine vascularization and arterial remodeling by MMPs and accumulation of ECM collagen. Blood pressure (BP) and fetal parameters were measured in normal Preg rats and RUPP rat model, and the uteri were assessed for vascularity, MMP levels, and collagen deposition. On gestational day 19, BP was higher, and the uterus weight, litter size, and pup weight were reduced in RUPP vs. Preg rats. Histology of uterine tissue sections showed reduced number (5.75 ± 0.95 vs. 11.50 ± 0.87) and size (0.05 ± 0.01 vs. 0.12 ± 0.02 mm2) of uterine spiral arterioles in RUPP vs. Preg rats. Immunohistochemistry showed localization of endothelial cell marker cluster of differentiation 31 (CD31) and smooth muscle marker α-actin in uterine arteriolar wall and confirmed decreased number/size of uterine arterioles in RUPP rats. The cytotrophoblast marker cytokeratin-7 showed less staining and invasion of spiral arteries in the deep decidua of RUPP vs. Preg rats. Uterine arteries showed less expansion in response to increases in intraluminal pressure in RUPP vs. Preg rats. Western blot analysis, gelatin zymography, and immunohistochemistry showed decreases in MMP-2 and MMP-9 and increases in the MMP substrate collagen-IV in uterus and uterine arteries of RUPP vs. those in Preg rats. The results suggest decreased number, size and expansiveness of spiral and uterine arteries with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg. Decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could be contributing mechanisms to uteroplacental ischemia in HTN-Preg and preeclampsia. NEW & NOTEWORTHY Preeclampsia is a pregnancy-related disorder in which initial inadequate placentation and RUPP cause the release of cytoactive factors and trigger a ceaseless cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent/depth of uterine vascularization and the driving proteolytic enzymes and ECM proteins are unclear. This study shows decreased number, size, and expansiveness of uterine spiral arteries, with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg rats. The decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could contribute to progressive uteroplacental ischemia in HTN-Preg and preeclampsia.

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EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

Reproduction ◽

10.1530/rep.1.00234 ◽

2004 ◽

Vol 128 (3) ◽

pp. 355-363 ◽

Cited By ~ 94

Author(s):

Q Qiu ◽

M Yang ◽

B K Tsang ◽

A Gruslin

Keyword(s):

Tissue Inhibitor Of Metalloproteinase ◽

Mitogen Activated Protein Kinase ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Signalling Pathways ◽

Placental Development ◽

Mapk Pathways ◽

Erk Phosphorylation ◽

Gene And Protein Expression ◽

Extravillous Trophoblasts

Epidermal growth factor (EGF) is present in the maternal-fetal environment and has an important role in placental development. Matrix metalloproteinase-9 (MMP-9) expression/activation is a pre-requisite in extravillous trophoblast invasion. Whereas EGF up-regulates MMP-9 activity in a variety of cell types, there is no direct evidence for the stimulation of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion by EGF in extravillous trophoblasts. In addition, the signalling pathways involved in this regulation are not clear. In the present study, we have examined the possible involvement of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in the regulation of the MMP-9/TIMP-1 system by EGFin vitro. We used a well-established invasive extravillous trophoblast cell line (HTR8/Svneo) and measured gene and protein expression by semi-quantitative RT-PCR and western analysis respectively. MMP activity was determined by zymography. We showed for the first time that EGF activated both PI3K/Akt and MAPK/extracellular-signal regulated kinase (ERK) signalling in HTR8/SVneo, and increased both MMP-9 and TIMP-1 mRNAs and protein concentrations. Interfering with either signalling pathway via PI3K inhibitor LY294002 or MEK inhibitor U0126 in EGF-stimulated HTR8/SVneo cells blocked the induction of MMP-9 and TIMP-1. LY294002 inhibited Akt phosphorylation, but had no effect on ERK phosphorylation; U0126 suppressed ERK phosphorylation without interfering with the phosphorylation of Akt. In addition, expression of constitutively active Akt (Myr-Akt1, Myr-Akt2, Myr-Akt3) was not sufficient to induce proMMP-9 and TIMP-1 secretion. Our results suggest that the activation of both PI3K and MAPK pathways in extravillous trophoblasts is necessary for the up-regulation of MMP-9 and TIMP-1 expression by EGF.

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