scholarly journals Overexpression of the Soluble Vascular Endothelial Growth Factor Receptor in Preeclamptic Patients: Pathophysiological Consequences

2003 ◽  
Vol 88 (11) ◽  
pp. 5555-5563 ◽  
Author(s):  
Vassilis Tsatsaris ◽  
Frederic Goffin ◽  
Carine Munaut ◽  
Jean-François Brichant ◽  
Marie-Rose Pignon ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Vegf Receptor ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Membrane Bound ◽  
Endothelial Growth Factor

Abstract Several growth factors such as vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are involved in the placental vascular development. We investigated whether dysregulation in the VEGF family may explain the defective uteroplacental vascularization characterizing preeclampsia. We compared pregnancies complicated by early onset severe preeclampsia or intrauterine growth retardation to normal pregnancies. Maternal plasma, placentas, and placental bed biopsies were collected. The mRNA levels of VEGF-A, PlGF, and their receptors were quantified in placentas and placental beds. Levels of VEGF-A, PlGF, and soluble VEGF receptor (VEGFR) were assessed in maternal plasma. In compromised pregnancies, elevated levels of VEGF-A and VEGFR-1 mRNAs may reflect the hypoxic status of the placenta. On contrast, the membrane-bound VEGFR-1 was decreased in the placental bed of preeclamptic patients. Preeclampsia was associated with low levels of circulating PlGF and increased levels of total VEGF-A and soluble VEGFR-1. Free VEGF-A was undetectable in maternal blood. Immunohistochemical studies revealed that VEGF-A and PlGF were localized in trophoblastic cells. Altogether, our results suggest two different pathophysiological mechanisms associated with preeclampsia. The first one is related to an overproduction of competitive soluble VEGFR-1 that may lead to suppression of VEGF-A and PlGF effects. The second one is the down-regulation of its membrane bound form (VEGFR-1) in the placental bed, which may result in the defective uteroplacental development.

149 EXPRESSION OF ANGIOGENIC FACTORS AND THEIR MAJOR RECEPTORS IN THE SHEEP PLACENTA THROUGHOUT THE EARLY PREGNANCY

2006 ◽  
Vol 18 (2) ◽  
pp. 182
Author(s):  
P. P. Borowicz ◽  
D. A. Redmer ◽  
A. T. Grazul-Bilska ◽  
G. Ptak ◽  
P. Loi ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Angiogenic Factors ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Fibroblast Growth ◽  
Mrna Concentration ◽  
Endothelial Growth Factor

Embryonic losses are high in mammals, with more than 30% of fertilized eggs not resulting in an offspring. The development of the placenta is critical for normal fetal growth and development as it provides for exchange of respiratory gases, nutrients, and wastes between the fetal and maternal systems. Placental vascular development determines the rate of placental blood flow, which is a primary determinant of placental function. Recent studies suggest that vascular endothelial growth factor (VEGF), its receptors (VEGFR), along with angiopoietins (Ang-1 and Ang-2) and their common receptor Tie-2, are major placental angiogenic factors, along with fibroblast growth factor-2 (FGF-2) and its receptor (FGFR). To evaluate the patterns of placental expression of these factors during early placental development, gravid uteri were obtained from ewes (n = 6 per day) on Days 12, 18, 24, 30, and 40 of gestation (day of mating = Day 0). At slaughter the uterine and embryonic tissues were weighed and representative samples of utero-placenta (CAR - caruncle, maternal placenta; ICAR - intracarunclar, endometrium; FM, fetal membranes) were snap frozen on dry ice and analyzed for relative mRNA levels by real-time RT-PCR (ABI Prism 7000, Sequence Detection System, Applied Biosystems, Monza, Italy) of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), receptor for both angiopoietins (Tie-2), fibroblast growth factor-2 (FGF-2), and fibroblast growth factor receptor (FGFR). The data were analyzed by nonlinear procedures using proc reg of SAS (SAS Institute, Inc., Cary, NC, USA). In CAR, the data showed the exponential increase from Days 12 to 40 in mRNA expression for VEGFR-1 (P < 0.0004; 0.04398e0.08794�day), VEGFR-2 (P < 0.01; 0.119208e0.06537�day), Ang-1 (P < 0.005; 0.00488e0.10881�day), Ang-2 (P < 0.0001; 0.01591e0.07864�day), Tie-2 (P < 0.03; 0.00488e0.06852�day), and FGFR (P < 0.08; 0.24577e0.04721�day). In the CAR, we also observed an exponential decrease in mRNA concentration for VEGF (P < 0.05; 28.193e-1.0719�day). In ICAR, we observed an exponential increase in mRNA concentration for VEGF (P < 0.05; 1.11685e0.06865�day), VEGFR-1 (P < 0.07; 0.09853e0.0383�day), Ang-1 (P < 0.09; 0.009318e0.05711�day), and Ang-2 (P < 0.004; 0.012647e0.09973�day). For FM, no changes in mRNA levels were observed from Days 12 to 40, but levels of all mRNAs were similar to those in CAR and ICAR. Based on the patterns of mRNA expression, these data indicate that these angiogenic factors may play an important role in early placental angiogenesis in sheep. This work was supported by NIH grant HL64141 to LPR and DAR.

scholarly journals Correlation of vascular endothelial growth factor and vascular endothelial growth factor receptor-1 levels in serum and thyroid nodules with histopathological and radiological variables

2019 ◽  
Vol 11 (01) ◽  
pp. 051-057 ◽  
Author(s):  
Gurkan Haytaoglu ◽  
Fatih Kuzu ◽  
Dilek Arpaci ◽  
Ayfer Altas ◽  
Murat Can ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Thyroid Nodules ◽  
Statistical Significance ◽  
Growth Factor Receptor ◽  
Needle Aspiration ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Number Of Patients ◽  
Endothelial Growth Factor

Abstract BACKGROUND/AIM: Vascular endothelial growth factor (VEGF) is a major cytokine in angiogenesis and has a role on aggressivity of various tumors. The expression of VEGF has been shown to increase in differential thyroid cancer. The aim of the study was to evaluate serum and intranodular VEGF (nVEGF) and VEGF receptor-1 (VEGFR-1) levels in patients with thyroid nodules and their relevance to ultrasonographic and pathological results. MATERIALS AND METHODS: A total of eighty patients were included in the study. Thyroid fine-needle aspiration biopsies were performed, and the levels of serum and nVEGF and VEGFR-1 were measured. Any possible correlations between serum and nVEGF, VEGFR-1, and biochemical/radiological variables were investigated. RESULTS: There were no significant differences between serum VEGF (sVEGF), nVEGF, sVEGFR-1, nVEGFR-1 levels, number of nodules, size of nodules, and benign and malignant ultrasonographic features. sVEGF and nVEGF were higher in malignant or suspicious nodules than that in benign nodules, but did not reach statistical significance (P > 0.05). sVEGFR-1 and nVEGFR-1 levels were higher in hyperthyroid patients than that in euthyroid patients (P < 0.05 and P = 0.003, respectively). nVEGFR-1 level was higher in hypothyroid patients than that in euthyroid patients (P = 0.016). sVEGF level was found to be higher in hyperactive nodules than that in others. Both sVEGFR-1 (P = 0.008) and nVEGF levels (P = 0.01) significantly increased with increasing age. nVEGFR-1 decreased with increasing body mass index (BMI) (P = 0.004). CONCLUSIONS: Our study showed the relationships of sVEGF, nVEGF, sVEGFR-1, and nVEGFR-1 levels with age, gender, BMI, and hyperthyroidism. To determine the role of VEGF/VEGFR-1 in thyroid nodules, further studies are required with a large number of patients.

Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation

2015 ◽  
Vol 113 (02) ◽  
pp. 329-337 ◽  
Author(s):  
Peter W. Hewett ◽  
Takeshi Fujisawa ◽  
Samir Sissaoui ◽  
Meng Cai ◽  
Geraldine Gueron ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Carbon Monoxide ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
Tube Formation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Sprouting Angiogenesis ◽  
Endothelial Growth Factor

SummaryCarbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor-reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.

scholarly journals Tyrosine phosphorylation of the vascular endothelial-growth-factor receptor-2 (VEGFR-2) is modulated by Rho proteins

2000 ◽  
Vol 348 (2) ◽  
pp. 273-280 ◽  
Author(s):  
Denis GINGRAS ◽  
Sylvie LAMY ◽  
Richard BÉLIVEAU
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Growth Factor Receptor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Rho Proteins ◽  
Transient Overexpression ◽  
Endothelial Growth Factor ◽  
Stimulation Of

The effects of Rho-specific modifying toxins on the tyrosine phosphorylation of endothelial cell proteins were investigated. Incubation of the cells with the Rho-activating toxin cytotoxic necrotizing factor 1 (CNF1) induced a marked increase in the tyrosine phosphorylation of a number of signalling intermediates of the vascular endothelial growth factor (VEGF)-mediated cascade, including focal adhesion kinase, paxillin, phospholipase Cγ1 and a Shc-associated protein of 195 kDa. Both CNF1- and VEGF-dependent tyrosine phosphorylation of these proteins were significantly reduced by prior incubation with C3 transferase, a known inhibitor of RhoA function, suggesting a Rho-dependent mechanism. The stimulation of endothelial cells with CNF1 resulted in a marked increase in the tyrosine phosphorylation of the VEGF receptor (VEGFR)-2, which was correlated with a stimulation of its kinase activity and with its association with downstream tyrosine phosphorylated proteins. The stimulatory effect of CNF1 was specific for VEGFR-2 since the phosphotyrosine content of VEGFR-1 was not affected by the toxin. Transient overexpression of a dominant-active RhoA mutant also induced an increase in the tyrosine phosphorylation of the VEGFR-2, whereas overexpression of a dominant-inactive form of the protein was without effect. Taken together, these results indicate that Rho proteins may play an important role in angiogenesis by modulating the tyrosine phosphorylation levels of VEGFR-2.

scholarly journals Low-Dose Dopamine Agonist Administration Blocks Vascular Endothelial Growth Factor (VEGF)-Mediated Vascular Hyperpermeability without Altering VEGF Receptor 2-Dependent Luteal Angiogenesis in a Rat Ovarian Hyperstimulation Model

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5400-5411 ◽  
Author(s):  
Raul Gomez ◽  
Miguel Gonzalez-Izquierdo ◽  
Ralf C. Zimmermann ◽  
Edurne Novella-Maestre ◽  
Isabel Alonso-Muriel ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Low Dose ◽  
Specific Treatment ◽  
Vegf Receptor ◽  
Ovarian Hyperstimulation ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Serum Progesterone ◽  
Endothelial Growth Factor

No specific treatment is available for ovarian hyperstimulation syndrome (OHSS), the most important complication in infertile women treated with gonadotropins. OHSS is caused by increased vascular permeability (VP) through ovarian hypersecretion of vascular endothelial growth factor (VEGF)-activating VEGF receptor 2 (VEGFR-2). We previously demonstrated in an OHSS rodent model that increased VP was prevented by inactivating VEGFR-2 with a receptor antagonist (SU5416). However, due to its toxicity (thromboembolism) and disruption of VEGFR-2-dependent angiogenic processes critical for pregnancy, this kind of compound cannot be used clinically to prevent OHSS. Dopamine receptor 2 (Dp-r2) agonists, used in the treatment of human hyperprolactinemia including pregnancy, inhibit VEGFR-2-dependent VP and angiogenesis when administered at high doses in animal cancer models. To test whether VEGFR-2-dependent VP and angiogenesis could be segregated in a dose-dependent fashion with the Dp-r2 agonist cabergoline, a well-established OHSS rat model supplemented with prolactin was used. A 100 μg/kg low-dose Dp-r2 agonist cabergoline reversed VEGFR-2-dependent VP without affecting luteal angiogenesis through partial inhibition of ovarian VEGFR-2 phosphorylation levels. No luteolytic effects (serum progesterone levels and luteal apoptosis unaffected) were observed. Cabergoline administration also did not affect VEGF/VEGFR-2 ovarian mRNA levels. Results in the animal model and the safe clinical profile of Dp-r2 agonists encouraged us to administer cabergoline to oocyte donors at high risk for developing the syndrome. Prophylactic administration of cabergoline (5–10 μg/kg·d) decreased the occurrence of OHSS from 65% (controls) to 25% (treatment). Therefore, a specific, safe treatment for OHSS is now available.

Catalytically inactive phospholipase A2 homologue binds to vascular endothelial growth factor receptor-2 via a C-terminal loop region

2008 ◽  
Vol 411 (3) ◽  
pp. 515-522 ◽  
Author(s):  
Daisuke Fujisawa ◽  
Yasuo Yamazaki ◽  
Bruno Lomonte ◽  
Takashi Morita
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Phospholipase A2 ◽  
Growth Factor Receptor ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Loop Region ◽  
Terminal Loop ◽  
Endothelial Growth Factor

VEGF (vascular endothelial growth factor) regulates neovascularization through binding to its receptor KDR (kinase insert domain-containing receptor; VEGF receptor-2). We recently identified a catalytically inactive PLA2 (phospholipase A2) homologue (KDR-bp) in the venom of eastern cottonmouth (Agkistrodon piscivorus piscivorus) as a third KDR-binding protein, in addition to VEGF165 and tissue inhibitor of metalloproteinase-3. KDR-bp binds to the extracellular domain of KDR with a Kd of 10−8 M, resulting in specific blockade of endothelial cell growth induced by VEGF165. Inactive PLA2 homologues are widely distributed in the venoms of Viperidae snakes and are known to act as myotoxins. In the present study, we demonstrated that KDR-binding ability is a common characteristic for inactive PLA2 homologues in snake venom, but not for active PLA2s such as neurotoxic and platelet aggregation-modulating PLA2s. To understand better the KDR and KDR-bp interaction, we resolved the binding region of KDR-bp using eight synthetic peptides designed based on the structure of KDR-bp. A synthetic peptide based on the structure of the C-terminal loop region of KDR-bp showed high affinity for KDR, but other peptides did not, suggesting that the C-terminal loop region of KDR-bp is involved in the interaction with KDR. The results of the present study provide insight into the binding of inactive PLA2 homologues to KDR, and may also assist in the design of novel anti-KDR molecules for anti-angiogenic therapy.

Abstract 3302: Vascular Endothelial Growth Factor Receptor Inhibition Impairs Intracerebral Hemorrhage-induced angiogenesis

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Han-Jin Cui ◽  
Qi-Ting Liu ◽  
Hua-Jun Zhou ◽  
TAO TANG
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Intracerebral Hemorrhage ◽  
Growth Factor Receptor ◽  
Treated Group ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Sham Control ◽  
Receptor Inhibition ◽  
Endothelial Growth Factor

Background and purpose: Our previous work has proved that Intracerebral hemorrhage (ICH) induces angiogenesis, accompanied by upregulation of vascular endothelial growth factor (VEGF) and its receptors. As the most potent mitogen of endothelial cells (ECs), VEGF must bind to its receptor_vascular endothelial growth factor receptor-2, to make it be phosphorylated, which plays the roles in promoting proliferation, migration, survival of ECs. In this study, our purpose is to investigate the effect of VEGF receptor inhibition on angiogenesis after ICH. Method: Fifteen Kunming mice were randomly divided into 3 groups, including sham control (n=5), ICH group (n=5), and SU5416-treated group (n=5). ICH model was induced by injection collagenase type VII into right globus pallidus stereotaxically. SU5416-treated group was injected by SU5416 (10 mg/kg per dose) intraperitoneally after ICH induction. Intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) was used to label new-born ECs. Neurological severity score (NSS), corner turn test and foot-fault test were used to investigate the neurological function at 1d, 3d and 7d following the surgery. Angiogenesis and the level of p-VEGFR-2 were evaluated at 7d by immunohistochemistry. Results: At 1d, there is no difference between the two ICH-induced groups in NSS, corner turn test, foot-fault test; at 3d and 7d, the NSS in ICH group is significantly lower than that of SU5416-treated group ( P <0.05), and the times for right-turn and foot-fault in ICH group are notably fewer than those of SU5416-treated group ( P <0.05). At 7d, no expression of p-VEGFR-2 was detected in sham control animals, while the expression of p-VEGFR-2 in ICH group is notably higher than that in SU5416-treated group ( P <0.05); and the expression of p-VEGFR-2 is located in vWF-immunoreactive ECs; there is no BrdU-labeled nuclear in vessels observed in sham-control mice, but BrdU-labeled nuclei in vessels in ICH group are remarkably more than those in SU5416-treated group ( P <0.05). Conclusions: Activation of VEGFR-2 is an important mechanism for angiogenesis after ICH, which is related with the recovery of neurological behavioral function.

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