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

ABSTRACT: 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.

SUBMITTER: Parchem JG

PROVIDER: S-EPMC6205389 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Parchem Jacqueline G JG Kanasaki Keizo K Kanasaki Megumi M Sugimoto Hikaru H Xie Liang L Hamano Yuki Y Lee Soo Bong SB Gattone Vincent H VH Parry Samuel S Strauss Jerome F JF Garovic Vesna D VD McElrath Thomas F TF Lu Karen H KH Sibai Baha M BM LeBleu Valerie S VS Carmeliet Peter P Kalluri Raghu R

The Journal of clinical investigation 20181008 11

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 Pl ...[more]

PMID: 30179860

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Project description:ObjectiveMost anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.MethodsPregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.ResultsUltrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3 ± 51.7 μg/mg vs. 19.3 ± 5.6 μg/mg, p = 4.4 x 10(-2); GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2 x 10(-2)). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).ConclusionsA mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the in vivo pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.

Project description:BackgroundThe fullPIERS risk prediction model was developed to identify which women admitted with confirmed diagnosis of preeclampsia are at highest risk of developing serious maternal complications. The model discriminates well between women who develop (vs. those who do not) adverse maternal outcomes. It has been externally validated in several populations. We assessed whether placental growth factor (PlGF), a biomarker associated with preeclampsia risk, adds incremental value to the fullPIERS model.MethodsUsing a cohort of women admitted into tertiary hospitals in well-resourced settings (the USA and Canada), between May 2010 to February 2012, we evaluated the incremental value of PlGF added to fullPIERS for prediction of adverse maternal outcomes within 48 h after admission with confirmed preeclampsia. The discriminatory performance of PlGF and the fullPIERS model were assessed in this cohort using the area under the receiver's operating characteristic curve (AUROC) while the extended model (fullPIERS +PlGF) was assessed based on net reclassification index (NRI) and integrated discrimination improvement (IDI) performances.ResultsIn a cohort of 541 women delivered shortly (< 1 week) after presentation, 8.1% experienced an adverse maternal outcome within 48 h of admission. Prediction of adverse maternal outcomes was not improved by addition of PlGF to fullPIERS (NRI: -8.7, IDI - 0.06). Discriminatory performance (AUROC) was 0.67 [95%CI: 0.59-0.75] for fullPIERS only and 0.67 [95%CI: 0.58-0.76]) for fullPIERS extended with PlGF, a performance worse than previously documented in fullPIERS external validation studies (AUROC > 0.75).ConclusionsWhile fullPIERS model performance may have been affected by differences in healthcare context between this study cohort and the model development and validation cohorts, future studies are required to confirm whether PlGF adds incremental benefit to the fullPIERS model for prediction of adverse maternal outcomes in preeclampsia in settings where expectant management is practiced.

Project description:ImportanceIt remains unknown whether neurodevelopmental impairments are directly associated with the structural development of the brain in offspring with fetal growth restriction (FGR) and mothers with preeclampsia (PE) or gestational hypertension (GH).ObjectivesTo assess whether fetal corpus callosum (CC) development differed among pregnancies with PE or GH with FGR, pregnancies with PE or GH without FGR, and normotensive pregnancies, particularly the severity of maternal disease and FGR, and to identify the association between adverse perinatal outcomes and structural development of the CC in fetuses with FGR in pregnancies with PE or GH.Design, setting, and participantsThis retrospective matched case-control study was conducted between January 1, 2014, and January 31, 2021, at Women's Hospital, Zhejiang University School of Medicine in Hangzhou, China. The participant group included cases of singleton pregnancies with PE or GH with FGR; the control groups included cases with PG or GH without FGR and cases with paired normotensive pregnancy.ExposuresMaternal PE or GH and FGR.Main outcomes and measuresThe length, thickness, total area, subdivision areas, and apparent diffusion coefficient (ADC) values of fetal CC were measured on magnetic resonance imaging (MRI) and analyzed. The association between adverse perinatal outcomes and structural development of CC was further investigated.ResultsA total of 56 pregnant individuals with singleton pregnancies and PE or GH and fetuses with FGR were enrolled (maternal median [IQR] age, 29.0 [26.0-34.0] years; mean [SD] gestational age at MRI, 33.6 [2.5] weeks). Significant patterns of decreased median (IQR) fetal CC length (0.4284 [0.4079-0.4470] mm vs 0.4614 [0.4461-0.4944] mm, P < .001, vs 0.4591 [0.4310-0.4927] mm, P < .001) and mean (SD) CC total area (1.0779 [0.1931] mm2 vs 1.1896 [0.1803] mm2, P = .001, vs 1.1438 [0.1935] mm2, P = .02), adjusted for the cephalic index, was observed in cases of PE or GH with FGR compared with cases without FGR and cases with normotensive pregnancy. The splenium region of fetal CC also exhibited the distinct alterations in macrostructural development (with FGR: 0.3149 [0.0697] mm2 vs without FGR: 0.3727 [0.0698] mm2, P < .001, vs normotensive pregnancies: 0.3565 [0.0763] mm2, P < .001) and microstructural development (median [IQR] ADC values: 1.47 [1.38-1.57] × 10-3 mm2/s vs 1.57 [1.53-1.63] × 10-3 mm2/s, P = .009, vs 1.63 [1.50-1.70] × 10-3 mm2/s, P < .001) in all groups. Furthermore, significant associations were found between structural abnormality of the splenium region and adverse perinatal outcomes in the PE or GH with FGR group (mean [SD] ADC value: 1.40 [0.07] × 10-3 mm2/s; P = .04).Conclusions and relevanceResults of this study suggest that, in fetuses with FGR in pregnancies with PE or GH, decreased structural development of the CC, predominantly the splenium region, may be significantly associated with a higher risk of adverse perinatal outcomes and may be regarded as an MRI-based biomarker for better prenatal counseling and early management decisions.

Project description:BackgroundAngiogenic placental growth factor (PlGF) concentrations rise during pregnancy, peaking at the end of midpregnancy. Low PlGF concentrations during pregnancy are associated with pregnancy complications with recognized later-life cardiovascular risk. We hypothesized that low PlGF concentrations, especially in midpregnancy, identify not only a subset of women at risk for pregnancy complications but also women with greater cardiovascular risk factor burden after pregnancy regardless of pregnancy outcome.MethodsIn a population-based prospective cohort study of 5475 women, we computed gestational age-adjusted multiples of the medians of early pregnancy and midpregnancy PlGF concentrations. Information on pregnancy complications (preeclampsia, small for gestational age, and spontaneous preterm birth) was obtained from hospital registries. Six years after pregnancy, we measured maternal systolic and diastolic blood pressures, cardiac structure (aortic root diameter, left atrial diameter, left ventricular mass, and fractional shortening), carotid-femoral pulse wave velocity, and central retinal arteriolar and venular calibers. Blood pressure was also measured 9 years after pregnancy.ResultsWomen were on average 29.8 (SD, 5.2) years of age in pregnancy, were mostly European (55.2%), and 14.8% developed a pregnancy complication. Quartile analysis showed that especially women with midpregnancy PlGF in the lowest quartile (the low-PlGF subset) had a larger aortic root diameter (0.40 mm [95% CI, 0.08-0.73]), left atrial diameter (0.34 mm [95% CI, -0.09 to 0.78]), left ventricular mass (4.6 g [95% CI, 1.1-8.1]), and systolic blood pressure (2.3 mm Hg [95% CI, 0.93-3.6]) 6 years after pregnancy than women with the highest PlGF. Linear regression analysis showed that higher midpregnancy PlGF concentrations were associated with a smaller aortic root diameter (-0.24 mm [95% CI, -0.39 to -0.10]), smaller left atrial diameter (-0.75 mm [95% CI, -0.95 to -0.56]), lower left ventricular mass (-3.9 g [95% CI, -5.5 to -2.3]), and lower systolic blood pressure (-1.1 mm Hg [95% CI, -1.7 to -0.46]). These differences persisted after the exclusion of women with complicated pregnancies.ConclusionsWomen with low PlGF in midpregnancy have a greater aortic root diameter, left atrial diameter, and left ventricular mass and higher systolic blood pressure 6 and 9 years after pregnancy compared to women with higher PlGF, including women with uncomplicated pregnancies. The pathophysiological implications of lower PlGF concentrations in midpregnancy might provide insight into the identification of pathways contributing to greater cardiovascular risk factor burden.

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

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

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