scholarly journals Inhibition of Single Routes of Intracellular Signaling is Not Sufficient to Neutralize the Biphasic Disturbance of a Retinal Endothelial Cell Barrier Induced by VEGF-A165

2017 ◽  
Vol 42 (4) ◽  
pp. 1493-1513 ◽  
Author(s):  
Heidrun L. Deissler ◽  
Gerhard K. Lang ◽  
Gabriele E. Lang
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Early Response ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Retinal Endothelial Cell ◽  
Specific Receptors ◽  
Barrier Breakdown ◽  
High Concentrations ◽  
Endothelial Growth Factor

Background/Aims: Hallmark of diabetic macular edema is the enhanced permeability of retinal endothelial cells (REC) induced by vascular endothelial growth factor (VEGF-A165), which acts through activating specific receptors. To improve the predictability of inhibitors' potentials to block harmful effects of VEGF-A165, we investigated if its signaling pathways triggered in REC are redundant. Methods: Immortalized bovine REC monolayers were treated with inhibitors specific for various protein kinases in combination with VEGF-A165. Permeability was monitored continuously by measurements of the cell index (CI) to reveal even subtle and transient changes. Expression of tight junction (TJ) proteins was determined as additional indicator of barrier stability. Results: After a sharp but transient CI drop caused by VEGF-A165 early after its addition, further exposure resulted in a continuous CI decline over several days associated with loss of TJ protein claudin-1. Both phases were blocked by inhibition of VEGF receptor 2. Tested inhibitors of intracellular kinases had a limited or no effect, or were efficient only in certain phases of exposure to VEGF-A165, e.g. inhibiting protein kinase C only prevented the early response. High concentrations of some inhibitors even resulted in VEGF-independent barrier destabilization. Conclusions: Specific kinase inhibitors differently affect VEGF-A165-triggered processes in distinct phases of its action. VEGF-A165-initiated signaling is redundant and blocking of key proteins of single pathways is not sufficient to suppress REC barrier breakdown.

Abstract 337: Alternative Angiogenic Pathway Driven by Stimulus-Dependent Phosphorylation of Profilin-1

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yi Fan ◽  
Paul L Fox
Keyword(s):  
Blood Vessels ◽  
Intracellular Signaling ◽  
Tissue Repair ◽  
Actin Polymerization ◽  
Leading Edge ◽  
Actin Binding ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Post Injury ◽  
Endothelial Growth Factor

Angiogenesis, the outgrowth of new blood vessels from pre-existing ones, is fundamental to development and post-injury tissue repair. Vascular endothelial growth factor (VEGF)-A guides and enhances directional endothelial cell (EC) migration to initiate angiogenesis, which can be driven by a multistep signaling cascade that directs actin polymerization. Profilin-1 (Pfn-1) is an actin-binding protein that enhances actin filament formation and cell migration, but stimulus-dependent regulation of Pfn-1 has not been observed. Here, we show that VEGF-A-inducible phosphorylation of Pfn-1 at Tyr129 is critical for EC migration and angiogenesis. Chemotactic activation of VEGF receptor kinase-2 (VEGFR2) and its immediate downstream kinase Src directly induce Pfn-1 phosphorylation in the cell leading edge, promoting Pfn-1 binding to actin and actin polymerization. Interestingly, Pfn-1 phosphorylation is robustly and preferentially elevated in blood vessels during tissue repair after myocardial infarction (MI) in humans. Conditional endothelial knock-in of phosphorylation-deficient Y129F Pfn-1 mutant in mice reveals that Pfn-1 phosphorylation is required for VEGF-A-induced EC sprouting migration and critical for angiogenesis in response to wounding and ischemic injury, but not for developmental angiogenesis. Thus, VEGFR2/Src-mediated phosphorylation of Pfn-1 bypasses canonical, multistep intracellular signaling events to initiate EC migration and angiogenesis, and may serve as a selective therapeutic target for angiogenesis-related disorders including ischemic heart disease.

scholarly journals Overexpression of VEGF in Testis and Epididymis Causes Infertility in Transgenic Mice: Evidence for Nonendothelial Targets for VEGF

1998 ◽  
Vol 143 (6) ◽  
pp. 1705-1712 ◽  
Author(s):  
Eija I. Korpelainen ◽  
Marika J. Karkkainen ◽  
Auri Tenhunen ◽  
Merja Lakso ◽  
Heikki Rauvala ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Capillary Density ◽  
Target Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
High Concentrations ◽  
Mmtv Ltr ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability. However, VEGF may also target nonendothelial cells, as VEGF receptors and responsiveness have been detected for example in monocytes, and high concentrations of VEGF have been reported in human semen. In this work we present evidence that overexpression of VEGF in the testis and epididymis of transgenic mice under the mouse mammary tumor virus (MMTV) LTR promoter causes infertility. The testes of the transgenic mice exhibited spermatogenic arrest and increased capillary density. The ductus epididymidis was dilated, containing areas of epithelial hyperplasia. The number of subepithelial capillaries in the epididymis was also increased and these vessels were highly permeable as judged by the detection of extravasated fibrinogen products. Intriguingly, the expression of VEGF receptor-1 (VEGFR-1) was detected in certain spermatogenic cells in addition to vascular endothelium, and both VEGFR-1 and VEGFR-2 were also found in the Leydig cells of the testis. The infertility of the MMTV-VEGF male mice could thus result from VEGF acting on both endothelial and nonendothelial cells of the male genital tract. Taken together, these findings suggest that the VEGF transgene has nonendothelial target cells in the testis and that VEGF may regulate male fertility.

Synthesis, Characterization and Antiproliferative Activity Assessment of a Novel 1H-5-mercapto-1,2,4 Triazole Derivative

2017 ◽  
Vol 68 (4) ◽  
pp. 745-747 ◽  
Author(s):  
Marius Mioc ◽  
Sorin Avram ◽  
Vasile Bercean ◽  
Mihaela Balan Porcarasu ◽  
Codruta Soica ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Biological Activities ◽  
Cancer Cell Line ◽  
Vascular Endothelial ◽  
Triazole Derivative ◽  
Activity Assessment ◽  
Wide Range ◽  
Specific Receptors ◽  
Endothelial Growth Factor ◽  
Selection Of

Angiogenesis plays an important function in tumor proliferation, one of the main angiogenic promoters being the vascular endothelial growth factor (VEGF) which activates specific receptors, particularly VEGFR-2. Thus, VEGFR-2 has become an essential therapeutic target in the development of new antitumor drugs. 1,2,4-triazoles show a wide range of biological activities, including antitumor effect, which was documented by numerous reports. In the current study the selection of 5-mercapto-1,2,4-triazole structure (1H-3-styryl-5-benzylidenehydrazino-carbonyl-methylsulfanil-1,2,4-triazole, Tz3a.7) was conducted based on molecular docking that emphasized it as suitable ligand for VEGFR-2 and EGFR1 receptors. Compound Tz3a.7 was synthesized and physicochemically and biologically evaluated thus revealing a moderate antiproliferative activity against breast cancer cell line MDA-MB-231.

Expression Profile of VEGF-C, VEGF-D, and VEGFR-3 in Different Grades of Endometrial Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 1004-1010
Author(s):  
Marcin Oplawski ◽  
Konrad Dziobek ◽  
Nikola Zmarzły ◽  
Beniamin Grabarek ◽  
Tomasz Halski ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Optical Density ◽  
Metastatic Potential ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Tumor Lymphangiogenesis ◽  
Neoplastic Process ◽  
The One ◽  
Post Hoc ◽  
Endothelial Growth Factor

Background: Vascular endothelial growth factor (VEGF)-C, -D, and VEGF receptor-3 are proteins characterized as crucial for tumor lymphangiogenesis. It is accompanied by angiogenesis during wound healing, but also in the neoplastic process. The research studies have shown that the lymphatic system plays a key role in the progression of carcinogenesis. Objective: The aim of this study was to evaluate changes in the expression of VEGF-C, VEGF-D and VEGFR-3 in different grades of endometrial cancer (G1-G3). Methods: The study included 45 patients diagnosed with endometrial cancer (G1=17; G2=15; G3=13) and 15 patients without neoplastic changes. The expression of VEGF-C, VEGF-D, and VEGFR-3 was assessed using microarray technique and immunohistochemistry. Statistical analysis was performed using the one-way ANOVA and Tukey's post-hoc test. Results: Statistically significant changes in the expression at the transcriptome level were found only in the case of VEGF-C (G1 vs. C, fold change - FC = -1.15; G2 vs. C, FC = -2.33; G3 vs. C, FC = - 1.68). However, VEGF-D and VEGFR-3 were expressed at the protein level. Analysis of VEGF-D expression showed that the optical density of the reaction product in G1 reached 101.7, while the values in G2 and G3 were 142.7 and 184.4, respectively. For VEGF-R3, the optical density of the reaction product reached the following levels: 72 in control, 118.77 in G1, 145.8 in G2, and 170.9 in G3. Conclusion: : An increase in VEGF-D and VEGFR-3 levels may indicate that VEGF-D-dependent processes are intensified along with the dedifferentiation of tumor cells. The lack of VEGF-C expression in endometrial cancer samples may suggest that this tumor is characterized by a different mechanism of metastasis than EMT. Our study emphasizes that when analyzing the metastatic potential of cancer, the expression of more than one factor should be taken into account.

scholarly journals Lipid Raft Association Stabilizes VEGF Receptor 2 in Endothelial Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 798
Author(s):  
Ibukunoluwapo O. Zabroski ◽  
Matthew A. Nugent
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Lipid Rafts ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Potential Mechanism ◽  
Lysosomal Degradation ◽  
Extracellular Signal ◽  
The Stability ◽  
Endothelial Growth Factor

The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-β-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers.

scholarly journals Perforation of the Small Intestine after Introduction of Lenvatinib in a Patient with Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 14 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Naomi Suzuki ◽  
Kazuto Tajiri ◽  
Yuka Futsukaichi ◽  
Shinichi Tanaka ◽  
Aiko Murayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Intestine ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Vascular Endothelial ◽  
First Line ◽  
Endothelial Growth Factor ◽  
Line Standard

Lenvatinib is a first-line standard treatment for advanced hepatocellular carcinoma (HCC) with better anti-tumor effects than sorafenib, as shown by greater inhibition of the kinases of fibroblast growth factor receptor and vascular endothelial growth factor (VEGF) receptor. This report describes a patient with advanced HCC who experienced perforation of the small intestine 1 month after starting the treatment with lenvatinib. This patient likely had partial necrosis of a metastasis to the small intestine before starting lenvatinib treatment, with subsequent ischemic changes leading to perforation of the small intestine. Although metastasis of HCC to the small intestine is rare, patients with these metastases should be regarded as being at risk for perforation during lenvatinib treatment.

Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism

2007 ◽  
Vol 293 (1) ◽  
pp. H709-H718 ◽  
Author(s):  
Jerome W. Breslin ◽  
Nathalie Gaudreault ◽  
Katherine D. Watson ◽  
Rashell Reynoso ◽  
Sarah Y. Yuan ◽  
...  
Keyword(s):  
Stroke Volume ◽  
Stroke Volume Index ◽  
Volume Index ◽  
Flow Index ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Contraction Frequency ◽  
Pump Activity ◽  
Endothelial Growth Factor ◽  
Arteriolar Diameter

Vascular endothelial growth factor (VEGF)-C plays an important role in lymphangiogenesis; however, functional responses of lymphatic vessels to VEGF-C have not been characterized. We tested the hypothesis that VEGF-C-induced activation of VEGF receptor (VEGFR)-3 increases lymphatic pump output. We examined the in vivo pump activity of rat mesenteric collecting lymphatics using intravital microscopy during basal conditions and during treatment with 1 nM recombinant VEGF-C, the selective VEGFR-3 agonist VEGF-Cys156Ser mutation (C156S; 1 nM), or 0.1 nM VEGF-A. Their specific responses were also analyzed during selective inhibition of VEGFR-3 with MAZ-51. Contraction frequency, end-diastolic diameter, end-systolic diameter, stroke volume index, pump flow index, and ejection fraction were evaluated. We also assessed arteriolar diameter and microvascular extravasation of FITC-albumin. The results show that both VEGF-C and VEGF-C156S significantly increased contraction frequency, end-diastolic diameter, stroke volume index, and pump flow index in a time-dependent manner. VEGF-A caused a different response characterized by a significantly increased stroke volume after 30 min of treatment. MAZ-51 (5 μM) caused tonic constriction and decreased contraction frequency. In addition, 0.5 and 5 μM MAZ-51 attenuated VEGF-C- and VEGF-C156S-induced lymphatic pump activation. VEGF-A caused vasodilation of arterioles, whereas VEGF-C and VEGF-C156S did not significantly alter arteriolar diameter. Also, VEGF-A and VEGF-C caused increased microvascular permeability, whereas VEGF-C156S did not. Our results demonstrate that VEGF-C increases lymphatic pumping through VEGFR-3. Furthermore, changes in microvascular hemodynamics are not required for VEGFR-3-mediated changes in lymphatic pump activity.

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