Angiogenic capacity in pre-eclampsia and uncomplicated pregnancy estimated by assay of angiogenic proteins and an in vitro vasculogenesis/angiogenesis test

Virtanen, Arja; Huttala, Outi; Tihtonen, Kati; Toimela, Tarja; Heinonen, Tuula; Uotila, Jukka

doi:10.1007/s10456-018-9637-2

Cited by 8 publications

(8 citation statements)

References 29 publications

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“…Presumably, diminished CSF concentrations in PE and HELLP syndrome imply fewer maternal brain adaptations. Virtanen et al observed an inhibitory effect on tubule formation in third trimester preeclamptic women 17 . Serum concentrations of angiogenic factors sFlt-1 levels were higher and PlGF were lower in third trimester preeclamptic women compared to healthy controls with increasing sFlt-1/PlGF ratio between the first and the third trimester 18 .…”

Section: Discussionmentioning

confidence: 97%

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Lederer

Schaffenrath

Alomar-Dominguez

et al. 2020

Sci Rep

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During pregnancy, substantial alterations in cerebral plasticity, vascular remodeling and neuronal growth occur in the maternal brain. We investigated whether concentrations of selected neurodiagnostic biomarkers in the cerebrospinal fluid of women with preeclampsia/HELLP syndrome differ from those in healthy controls using enzyme-linked immunosorbent assay technique. We found that tau protein concentrations (p = 0.016) and phospho-tau/tau ratio (p < 0.001) in cerebrospinal fluid were significantly lower in 39 preeclamptic women compared to 44 healthy controls during third trimester of pregnancy. Beta-amyloid(1-40)/(1-42) ratio was significantly higher in HELLP syndrome than in severe preeclampsia (8.49 + 2.73 vs. 4.71 + 1.65; p = 0.007). We conclude that betaamyloid(1-40)/(1-42) ratio in cerebrospinal fluid can discriminate severe preeclampsia and HELLP syndrome. High beta-amyloid peptide and low tau protein concentrations are associated with impaired development of the materno-feto-placental unit and correlate with placental dysfunction. During pregnancy, the invasion of trophoblast cells into maternal tissue of the uterus and the conversion of spiral arteries into wide sinusoids with low resistance and high flow are paramount for normal placental development 1. In preeclampsia (PE) placental development is impaired by defective deep placentation, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and imbalanced angiogenesis 2. Altered expression of proteins comes along with excess of antiangiogenic substances such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) and decreased levels of proangiogenic substances like placental growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) 3. Ciampa et al. observed in 13 patients with PE altered concentrations of proteins related to signaling pathways important for vascular remodeling, inflammation, and neuronal growth 4. Recent studies have shown that PE shares pathophysiologic features with recognized misfolding disorders and aggregation of proteins 4-8. There are several dysregulated proteins in PE but it is not clear whether aggregated proteins induce defective trophoblast invasion 4. D'Souza et al. reported that neurotrophic factors influence the development of the materno-feto-placental unit during pregnancy 9. Altered blood-brain barrier and impaired cerebral autoregulation may affect erebral blood flow in the maternal brain 10. Aggregated beta-amyloid peptides were observed in PE as well as in Alzheimer's disease 7. The presence of beta-amyloid aggregates in placentas of women with PE and intrauterine growth restriction (IUGR) further supports the notion that this condition goes with protein conformational disorders 6,11. Moreover, it was observed that short peptides occupying the self-recognition sites of beta-amyloid inhibit beta-amyloid aggregation 8. The aim of this study was to determine whether CSF concentrations of beta-amyloid peptides and tau protein differ between women with PE...

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Section: Discussionmentioning

confidence: 97%

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Lederer

Schaffenrath

Alomar-Dominguez

et al. 2020

Sci Rep

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“…The specificity of the ELISA is supported by its strong correlation with the levels of bioactive vasoinhibin quantified using the HUVEC proliferation assay. Furthermore, the CAM angiogenesis assay supports the contribution of vasoinhibin to the antiangiogenic properties of the serum, which is characteristic of preeclampsia ( 40 ). The essential component of the ELISA is the vi-mab having no cross-reactivity with PRL ( Supplementary Figure S1 ) ( 31 ).…”

Section: Discussionmentioning

confidence: 67%

Immunometric and functional measurement of endogenous vasoinhibin in human sera

Zamora,

Harris,

Davies

et al. 2024

Front. Endocrinol.

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IntroductionCirculating levels of the antiangiogenic protein vasoinhibin, a fragment of prolactin, are of interest in vasoproliferative retinopathies, preeclampsia, and peripartum cardiomyopathy; however, it is difficult to determine the circulating levels of vasoinhibin due to the lack of quantitative assays. MethodsThis study used human serum samples to assess the concentration and bioactivity of vasoinhibin using a novel enzyme-linked immunosorbent assay (ELISA) for human vasoinhibin, which employs an anti-vasoinhibin monoclonal antibody, a human umbilical vein endothelial cell (HUVEC) proliferation assay, and a chick chorioallantoic membrane (CAM) angiogenesis assay. ResultsSerum samples from 17 pregnant women without (one group) and with preeclampsia and pregnancy induced hypertension (another group) demonstrated endogenous vasoinhibin concentrations in the range of 5–340 ng/ml. Immunoactive vasoinhibin levels were significantly higher in preeclampsia serum compared to healthy pregnancy serum (mean 63.09 ± 22.15 SD vs. 19.67 ± 13.34 ng/ml, p = 0.0003), as was the bioactive vasoinhibin level as determined by the HUVEC proliferation assay (56.12 ± 19.83 vs. 13.38 ± 4.88 ng/ml, p < 0.0001). There was a correlation between the concentration of vasoinhibin measured by ELISA and the HUVEC proliferation assay (Pearson r = 0.95, p < 0.0001). Healthy serum demonstrated a proangiogenic effect in the CAM assay (p < 0.05, compared to control), while serum from preeclamptic patients demonstrated an antiangiogenic effect (p < 0.05 vs. control), as did recombinant human vasoinhibin and a synthetic circular retro-inverse vasoinhibin analogue (CRIVi45-51). The antiangiogenic effects in the CAM assay and the inhibition of HUVEC proliferation were abolished by addition of the ELISA anti-vasoinhibin monoclonal antibody, but not by mouse IgG. DiscussionThese results demonstrate the first quantitation of endogenous vasoinhibin in human sera and the elevation of it levels and antiangiogenic activity in sera from women with preeclampsia. The development and implementation of a quantitative assay for vasoinhibin overcomes a long-standing barrier and suggests the thorough clinical verification of vasoinhibin as a relevant biomarker.

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“…Intra-laboratory validation has been performed for the hASC-HUVEC test (Environment Directorate, OECD), and good concordance in comparison with blood vessels in vivo has been observed [11]. We have previously utilized the present in vitro model to study maternal and umbilical sera in order to assess overall angiogenic capacity in PE and healthy pregnancies and to evaluate the effect of metformin on angiogenesis [14, 15, 18]. Since statins have reported to have anti-angiogenic effects in high doses, the pravastatin concentrations chosen for this study correspond to therapeutic and supratherapeutic levels in human.…”

Section: Discussionmentioning

confidence: 99%

“…Concentrations of haem oxygenase 1, endothelin-1, and angiopoietin-2 were determined by using ELISA kits according to the manufacturer’s instructions. The concentrations of tumour necrosis factor α (TNF-α), sFlt-1, placental growth factor (PlGF), vascular endothelial growth factor A, vascular cell adhesion molecule 1 (VCAM-1), interleukin-6 (IL-6), and soluble endoglin (sEng) were determined in all samples by using ProcartaPlex assays (Thermo Fisher Scientific), following the manufacturer’s protocols and as described earlier [14]. In addition, medium samples collected from the cell cultures on day 6 were analysed to determine concentrations of TNF-α, sFlt-1, PlGF, vascular endothelial growth factor A, VCAM-1, IL-6, and sEng.…”

Section: Methodsmentioning

confidence: 99%

“…To assess the direct effects of pravastatin on angiogenesis, tubule formation was first studied without maternal serum. The tests were performed as described earlier [14, 15] with modification of the concentrations of supplements. Briefly, a co-culture of hASCs (20,000 cells/cm 2 ) and HUVECs (4,000 cells/cm 2 ) was plated on 48-well plates on day 0.…”

Section: Methodsmentioning

confidence: 99%

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Angiogenic Effect of Pravastatin Alone and with Sera from Healthy and Complicated Pregnancies Studied by in vitro Vasculogenesis/Angiogenesis Assay

et al. 2021

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Objective: To determine the direct effect of pravastatin on angiogenesis and to study the interaction between pravastatin and maternal sera from women with early- or late-onset pre-eclampsia (PE), intrauterine growth restriction, or healthy pregnancy. Methods: We collected 5 maternal serum samples from each group. The effect of pravastatin on angiogenesis was assessed with and without maternal sera by quantifying tubule formation in a human-based in vitro assay. Pravastatin was added at 20, 1,000, and 8,000 ng/mL concentrations. Concentrations of angiogenic and inflammatory biomarkers in serum and in test medium after supplementation of serum alone and with pravastatin (1,000 ng/mL) were measured. Results: Therapeutic concentration of pravastatin (20 ng/mL) did not have significant direct effect on angiogenesis, but the highest concentrations inhibited angiogenesis. Pravastatin did not change the levels of biomarkers in the test media. There were no changes in angiogenesis when therapeutic dose of pravastatin was added with maternal sera, but there was a trend to wide individual variation towards enhanced angiogenesis, particularly in the early-onset PE group. Conclusions: At therapeutic concentration, pravastatin alone or with maternal sera has no significant effect on angiogenesis, but at high concentrations the effect seems to be anti-angiogenic estimated by in vitro assay.

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Angiogenic capacity in pre-eclampsia and uncomplicated pregnancy estimated by assay of angiogenic proteins and an in vitro vasculogenesis/angiogenesis test

Abstract: Third-trimester serum of pre-eclamptic patients is anti-angiogenic. This phenomenon is not yet present in the first trimester. Umbilical blood serum shows inhibitory effects on angiogenesis after normal as well as pre-eclamptic pregnancy.

Cited by 8 publications

References 29 publications

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Immunometric and functional measurement of endogenous vasoinhibin in human sera

Angiogenic Effect of Pravastatin Alone and with Sera from Healthy and Complicated Pregnancies Studied by in vitro Vasculogenesis/Angiogenesis Assay

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