Decreased expression of pigment epithelium derived factor (PEDF), an inhibitor of angiogenesis, in placentas of unexplained stillbirths

Plunkett, Beth A.; Fitchev, Philip; Doll, Jennifer A.; Gerber, Susan E.; Cornwell, Mona; Greenstein, Emily P.; Crawford, Susan E.

doi:10.1016/s1642-431x(12)60007-2

Cited by 11 publications

(6 citation statements)

References 22 publications

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“…The effect of PEDF to limit feto-placental angiogenesis may have implications for pregnancy pathologies that are related to altered feto-placental angiogenesis. Indeed, PEDF expression was decreased in total placental tissue after unexpected stillbirth, a condition associated with vasculopathy and increased angiogenesis [ 64 ]. Since we identified trophoblast as the major site of placental PEDF production, this finding provides indirect evidence that trophoblast-derived PEDF is secreted toward the feto-placental endothelium to regulate angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy

et al. 2016

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The rapidly expanding feto-placental vasculature needs tight control by paracrine and endocrine mechanisms. Here, we focused on paracrine influence by trophoblast, the placental epithelium. We aimed to identify differences in regulation of feto-placental angiogenesis in early versus late pregnancy. To this end, the effect of conditioned media (CM) from early and late pregnancy human trophoblast was tested on network formation, migration and proliferation of human feto-placental endothelial cells. Only CM of late pregnancy trophoblast reduced network formation and migration. Screening of trophoblast transcriptome for anti-angiogenic candidates identified pigment epithelium-derived factor (PEDF) with higher expression and protein secretion in late pregnancy trophoblast. Addition of a PEDF-neutralizing antibody restored the anti-angiogenic effect of CM from late pregnancy trophoblast. Notably, human recombinant PEDF reduced network formation only in combination with VEGF. Also in the CAM assay, the combination of PEDF with VEGF reduced branching of vessels below control levels. Analysis of phosphorylation of ERK1/2 and FAK, two key players in VEGF-induced proliferation and migration, revealed that PEDF altered VEGF signaling, while PEDF alone did not affect phosphorylation of ERK1/2 and FAK. These data suggest that the trophoblast-derived anti-angiogenic molecule PEDF is involved in restricting growth and expansion of the feto-placental endothelium predominantly in late pregnancy and targets to modulate the intracellular effect of VEGF.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-016-9513-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy

et al. 2016

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“…The strongest relationship was between leptin and PEDF in the offspring of DM mothers, wherein 38 % of the variation in leptin concentration was explained by PEDF level. Although the basis for this relationship is unclear, it could be reflect the need for the angiogenic properties of leptin to be balanced by the anti-angiogenic effects of PEDF in the placenta, a putative source of cord blood leptin and PEDF [ 10 , 29 ]. PEDF has been shown to inhibit leptin induced angiogenesis in vitro [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Pigment epithelial-derived factor (PEDF) is a serpin-like protein lacking inhibitory function that was selected for study because expression is known to be influenced by diabetes and obesity [ 2 , 3 ], circulating levels are related to vascular complications of diabetes and insulin sensitivity [ 4 – 6 ], and it is produced by adipose tissue, liver, and placenta [ 7 – 9 ]. One prior report found PEDF expression decreased in placentae from stillborn [ 10 ] and a pilot study noted increased cord blood levels in pre-eclampsia [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and Native American women with diabetes mellitus

Teague

Fields

Aston

et al. 2015

Reprod Biol Endocrinol

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BackgroundOffspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women.MethodsWe conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates.ResultsDM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort.ConclusionsMaternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

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“…There have been a number of studies investigating the relationship between placental angiogenesis, vascular remodeling, and stillbirth. In a study of 22 unexplained stillbirths and 44 age-matched live-born controls, stillbirth was associated with increased placental microvascular density, vasculopathy, and increased vascular permeability, 58 suggesting increased vascular remodeling in terminal stillbirth placentae. In contrast, in 1269 singleton women with samples collected between 30-34 weeks of gestation, a low PlGF/sFlt-1 ratio was associated with stillbirth.…”

Section: Commentmentioning

confidence: 99%

Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV

Conroy

McDonald

Gamble

et al. 2017

American Journal of Obstetrics and Gynecology

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BackgroundAngiogenic processes in the placenta are critical regulators of fetal growth and impact birth outcomes, but there are limited data documenting these processes in HIV-infected women or women from low-resource settings.ObjectiveWe sought to determine whether angiogenic factors are associated with adverse birth outcomes in HIV-infected pregnant women started on antiretroviral therapy.Study DesignThis is a secondary analysis of samples collected as part of a clinical trial randomizing pregnant women and adolescents infected with HIV to lopinavir/ritonavir-based (n = 166) or efavirenz-based (n = 160) antiretroviral therapy in Tororo, Uganda. Pregnant women living with HIV were enrolled between 12-28 weeks of gestation. Plasma samples were evaluated for angiogenic biomarkers (angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin) by enzyme-linked immunosorbent assay between: 16-<20, 20-<24, 24-<28, 28-<32, 32-<36, 36-<37 weeks of gestation. The primary outcome was preterm birth.ResultsIn all, 1115 plasma samples from 326 pregnant women and adolescents were evaluated. There were no differences in angiogenic factors according to antiretroviral therapy group (P > .05 for all). The incidence of adverse birth outcomes was 16.9% for spontaneous preterm births, 25.6% for small-for-gestational-age births, and 2.8% for stillbirth. We used linear mixed effect modelling to evaluate longitudinal changes in angiogenic factor concentrations between birth outcome groups adjusting for gestational age at venipuncture, maternal age, body mass index, gravidity, and the interaction between treatment arm and gestational age. Two angiogenic factors–soluble endoglin and placental growth factor–were associated with adverse birth outcomes. Significantly higher concentrations of soluble endoglin throughout gestation were found in study participants destined to deliver preterm [likelihood ratio test, χ2(1) = 12.28, P < .0005] and in those destined to have stillbirths [χ2(1) = 5.67, P < .02]. By contrast, significantly lower concentrations of placental growth factor throughout gestation were found in those destined to have small-for-gestational-age births [χ2(1) = 7.89, P < .005] and in those destined to have stillbirths [χ2(1) = 21.59, P < .0001].ConclusionAn antiangiogenic state in the second or third trimester is associated with adverse birth outcomes, including stillbirth in women and adolescents living with HIV and receiving antiretroviral therapy.

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Decreased expression of pigment epithelium derived factor (PEDF), an inhibitor of angiogenesis, in placentas of unexplained stillbirths

Cited by 11 publications

References 22 publications

Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy

Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy

Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and Native American women with diabetes mellitus

Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV

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