The immunohistochemical evaluation of VEGF in placenta biopsies of pregnancies complicated by preeclampsia

Akercan, Fuat; Çırpan, Teksin; Terek, Mustafa Coşan; Özçakır, Hasan Tayfun; Giray, Gülşen; Sağol, Sermet; Karadadaş, Nedim

doi:10.1007/s00404-007-0430-5

Cited by 35 publications

(22 citation statements)

References 30 publications

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“…In our study, the reduction in EGFL7 levels in PE was more pronounced as compared to VEGF levels (Fig. 5I), a growth factor whose implication in PE has been extensively studied by others, and found to be either decreased (Cooper et al, 1996; Lyall et al, 1997; Park et al, 2010) or increased (Akercan et al, 2008; Chung et al, 2004; Geva et al, 2002) in PE placentas. Thus, EGFL7 expression is significantly downregulated in both a mouse model of PE and human PE placentas.…”

Section: Resultssupporting

confidence: 63%

Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia

Lacko¹,

Massimiani²,

Sones³

et al. 2014

Mechanisms of Development

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The mammalian placenta is the site of nutrient and gas exchange between the mother and fetus, and is comprised of two principal cell types, trophoblasts and endothelial cells. Proper placental development requires invasion and differentiation of trophoblast cells, together with coordinated fetal vasculogenesis and maternal vascular remodeling. Disruption in these processes can result in placental pathologies such as preeclampsia (PE), a disease characterized by late gestational hypertension and proteinuria. Epidermal Growth Factor Like Domain 7 (EGFL7) is a largely endothelial-restricted secreted factor that is critical for embryonic vascular development, and functions by modulating the Notch signaling pathway. However, the role of EGFL7 in placental development remains unknown. In this study, we use mouse models and human placentas to begin to understand the role of EGFL7 during normal and pathological placentation. We show that Egfl7 is expressed by the endothelium of both the maternal and fetal vasculature throughout placental development. Importantly, we uncovered a previously unknown site of EGFL7 expression in the trophoblast cell lineage, including the trophectoderm, trophoblast stem cells, and placental trophoblasts. Our results demonstrate significantly reduced Egfl7 expression in human PE placentas, concurrent with a downregulation of Notch target genes. Moreover, using the BPH/5 mouse model of PE, we show that the downregulation of Egfl7 in compromised placentas occurs prior to the onset of characteristic maternal signs of PE. Together, our results implicate Egfl7 as a possible factor in normal placental development and in the etiology of PE.

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Section: Resultssupporting

confidence: 63%

Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia

Lacko¹,

Massimiani²,

Sones³

et al. 2014

Mechanisms of Development

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“…Despite several studies reporting that the levels of VEGF are increased in the placental tissue in preeclampsia (55, 56), our findings suggest that the secretion of VEGF by the placenta is not altered in preeclampsia. In combination with the increased placental production of sFlt-1 observed in preeclampsia, this supports that there is a shift toward more anti-angiogenic factors being released by the placenta during preeclampsia.…”

Section: Discussioncontrasting

confidence: 99%

Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia

et al. 2017

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Background/objectives: Preeclampsia is a life-threatening hypertensive disease affecting 3-5% of pregnancies. While the pathogenesis of preeclampsia remains unclear, it is known that placenta-derived factors trigger the disease by activating maternal endothelial cells prior to the onset of clinical symptoms. Extracellular vesicles (EVs) of different sizes extruded by the placenta may be one factor. The truncated/secreted form of Flt-1 (sFlt-1) has also been implicated in the pathogenesis of preeclampsia. We investigated whether placental EV production is altered in preeclampsia such that they induce endothelial cell activation, and whether (s)Flt-1 is involved.Methods: Macro-, micro-, and nano-vesicles were collected from normal and preeclamptic (PE) placental explants, and separated by differential centrifugation. The number and size of micro-and nano-vesicles was measured by nanoparticle tracking analysis and their ability to activate endothelial cells was quantified by endothelial cell intercellular adhesion molecule 1 expression and monocyte adhesion. The levels of Flt-1 were measured by western blots and ELISA.results: PE placentae extruded significantly more micro-and nano-vesicles than control placentae and the extruded micro-vesicles were larger than those from control placentae. Micro-and nano-vesicles from both first trimester and term human placentae carried Flt-1 and levels were significantly increased in EVs from severe, but not mild, PE compared to normotensive placentae. All fractions of EVs from PE placentae activated endothelial cells, and for micro-and nano-vesicles, activation was reduced in the presence of exogenous vascular endothelial growth factor (VEGF), a Flt-1 neutralizing antibody, or by pre-treatment with VEGF. While EV-bound VEGF constituted over 20% of the total detected VEGF secreted by PE and normotensive placentae, EV-bound Flt-1 did not significantly contribute to the total level of sFlt-1/Flt-1 released by human third trimester placentae.Discussion: Micro-and nano-vesicles extruded by human placentae carry Flt-1 across gestation and in severe preeclampsia, the levels of vesicle-bound Flt-1 are upregulated. All fractions of PE placental EVs activated endothelial cells and for micro-and nano-vesicles, this was in part due to the ability of EV-bound Flt-1 to sequester VEGF. That placental EVs can activate endothelial cells supports the contention that EVs are one placental toxin contributing to the pathogenesis of preeclampsia.

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“…Elevated serum VEGF levels may be involved in the activation and dysfunction of endothelial cells. 33 It is possible that the hyperdynamic circulation that characterizes the latent phase of preeclampsia causes vascular shear stress, which in turn increases the levels of circulating VEGF. Despite the increased Figure 4.…”

Section: Discussionmentioning

confidence: 99%

Effects of Angiogenic Factors, Antagonists, and Podocyte Injury on Development of Proteinuria in Preeclampsia

Chen

Zhang

et al. 2013

Reprod. Sci.

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Proteinuria is universal to all patients with preeclampsia. We examined the urinary podocytes in women with preeclampsia (n ¼ 14), gestational hypertension (n ¼ 14), and normal pregnancy. Maternal serum and urinary concentrations of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and the antiangiogenic factor soluble fms-like tyrosine kinase 1 (sFlt-1) were detected. These concentrations were used to evaluate the urinary excretion of podocytes and the alteration of angiogenic factors and to assess their relationships to proteinuria in preeclampsia. Our studies suggest that the urinary podocyte number and angiogenic factors are correlated with random urine albumin/creatinine ratio and blood pressure. Receiver-operating characteristic (ROC) curves of serum and urinary PlGF and the PlGF/sFlt-1 ratio as well as the presence of podocyturia confirmed their usefulness in distinguishing preeclamptic and normotensive pregnant women. In addition, combinations of serum or urinary PlGF or podocyturia tests in parallel or in series provided the best clue for identifying patients with preeclampsia. We considered that the dysregulation of angiogenic factors and its subsequent podocyte injury may contribute to the mechanism of proteinuria development in preeclampsia.

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The immunohistochemical evaluation of VEGF in placenta biopsies of pregnancies complicated by preeclampsia

Abstract: Immunostaining of VEGF is significantly higher in placenta biopsies of patients with preeclampsia.

Cited by 35 publications

References 30 publications

Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia

Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia

Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia

Effects of Angiogenic Factors, Antagonists, and Podocyte Injury on Development of Proteinuria in Preeclampsia

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