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 Lymphangiogenesis-independent resolution of experimental edema

2010 ◽  
Vol 299 (1) ◽  
pp. H46-H54 ◽  
Author(s):  
Emily L. Ongstad ◽  
Echoe M. Bouta ◽  
Jaclynn E. Roberts ◽  
Joseph S. Uzarski ◽  
Sara E. Gibbs ◽  
...  
Keyword(s):  
Tissue Repair ◽  
Wound Repair ◽  
Experimental Models ◽  
Blood Capillary ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Contributing Factors ◽  
Wound Site ◽  
Endothelial Growth Factor ◽  
Lymphatic Obstruction

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis, and excess VEGF-C has been shown to be ameliorative for edema produced by lymphatic obstruction in experimental models. However, it has recently been shown that edema can resolve in the mouse tail even in the complete absence of capillary lymphangiogenesis when distal lymph fluid crosses the regenerating wound site interstitially. This finding has raised questions about the action of VEGF-C/VEGF receptor (VEGFR) signaling during the resolution of experimental edema. Here, the roles of VEGFR-2 and VEGFR-3 signaling in edema resolution were explored. It was found that edema resolved following neutralization of either VEGFR-2 or VEGFR-3 in the mouse tail skin, which inhibited lymphangiogenesis. Neutralization of either VEGFR-2 or VEGFR-3 reduced angiogenesis at the site of obstruction at day 10 (9.2 ± 1.2% and 11.5 ± 1.0% blood capillary coverage, respectively) relative to controls (14.3 ± 1.5% blood capillary coverage). Combined VEGFR-2/-3 neutralization more strongly inhibited angiogenesis (6.9 ± 1.5% blood capillary coverage), leading to a reduced wound repair of the lymphatic obstruction and extended edema in the tail skin. In contrast, improved tissue repair of the obstruction site increased edema resolution. Macrophages in the swollen tissue were excluded as contributing factors in the VEGFR-dependent extended edema. These results support a role for VEGFR-2/-3-combined signaling in the resolution of experimental edema that is lymphangiogenesis independent.

VEGF promotes vascular sympathetic innervation

2008 ◽  
Vol 294 (6) ◽  
pp. H2646-H2652 ◽  
Author(s):  
Stephen B. Marko ◽  
Deborah H. Damon
Keyword(s):  
Blood Vessels ◽  
Sympathetic Innervation ◽  
Nerve Fibers ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Sympathetic Nerve Fibers ◽  
Endothelial Growth Factor ◽  
Immunohistochemical Analyses

The sympathetic nervous system, via postganglionic innervation of blood vessels and the heart, is an important determinant of cardiovascular function. The mechanisms underlying sympathetic innervation of targets are not fully understood. This study tests the hypothesis that target-derived vascular endothelial growth factor (VEGF) promotes sympathetic innervation of blood vessels. Western blot and immunohistochemical analyses indicate that VEGF is produced by vascular cells in arteries and that VEGF receptors are expressed on sympathetic nerve fibers innervating arteries. In vitro, exogenously added VEGF and VEGF produced by vascular smooth muscle cells (VSMCs) in sympathetic neurovascular cocultures inhibited semaphorin 3A (Sema3A)-induced collapse of sympathetic growth cones. In the absence of Sema3A, VEGF and VSMCs also increased growth cone area. These effects were mediated via VEGF receptor 1. In vivo, the neutralization of VEGF inhibited the reinnervation of denervated femoral arteries. These data demonstrate that target-derived VEGF plays a previously unrecognized role in promoting the growth of sympathetic axons.

Aspirin inhibits endothelial nitric oxide synthase (eNOS) and Flk-1 (vascular endothelial growth factor receptor-2) prior to rat colon tumour development

2004 ◽  
Vol 106 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Marta ESCRIBANO ◽  
Laura MOLERO ◽  
Antonio LÓPEZ-FARRÉ ◽  
Cynthia ABARRATEGUI ◽  
Carolina CARRASCO ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Caspase 3 ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Colonic Tissue ◽  
Colon Tumour ◽  
Endothelial Growth Factor

Formation of blood vessels is a fundamental element in the control of tumour growth in which vascular endothelial growth factor (VEGF) and nitric oxide (NO) have been demonstrated to be involved. Our aim was to analyse whether changes in the expression of endothelial NO synthase (eNOS) and VEGF in colonic tissue could be detected early and even before the identification of colon tumour-associated morphological modifications in azoxymethane-treated rats. We studied further whether aspirin treatment changed these parameters. An increased expression of both eNOS and VEGF in colonic tissue from azoxymethane-treated rats compared with that from control rats was found. Aspirin treatment (10 mg/kg of body weight per day) reduced eNOS expression, but failed to modify the expression of VEGF in the colonic tissue of azoxymethane-treated rats. No evidence of aberrant crypt formation or changes in the number of blood vessels were observed in the colon of any of the animals studied. Expression of the VEGF receptor Flk-1, but not Flt-1, was increased in colonic tissue of azoxymethane-treated rats compared with control rats. The expression of Flk-1 was mainly localized in the epithelial cells, particularly in the lower part of the crypt. Aspirin treatment reduced Flk-1 expression in both control and azoxymethane-treated rats. Caspase-3 activity, which has been considered as an apoptotic index, was almost undetectable in azoxymethane-treated rats. Aspirin treatment stimulated caspase-3 activity. Overexpression of eNOS, VEGF and its receptor Flk-1 occurred early after azoxymethane administration in rat colonic tissue, even before morphological changes associated with tumour generation were observed, and aspirin prevented the overexpression of both eNOS and VEGF receptor Flk-1.

scholarly journals Spreds Are Essential for Embryonic Lymphangiogenesis by Regulating Vascular Endothelial Growth Factor Receptor 3 Signaling

2007 ◽  
Vol 27 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Koji Taniguchi ◽  
Ri-ichiro Kohno ◽  
Toranoshin Ayada ◽  
Reiko Kato ◽  
Kenji Ichiyama ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Lymphatic Vessels ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Erk Activation ◽  
Factor C ◽  
Endothelial Growth Factor

ABSTRACT Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk −/− and SLP-76 −/− mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.

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.

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 Macrophage-Derived Inflammation Induces a Transcriptome Makeover in Mesenchymal Stromal Cells Enhancing Their Potential for Tissue Repair

2021 ◽  
Vol 22 (2) ◽  
pp. 781
Author(s):  
Inés Maldonado-Lasunción ◽  
Nick O’Neill ◽  
Oliver Umland ◽  
Joost Verhaagen ◽  
Martin Oudega
Keyword(s):  
Growth Factor ◽  
Tissue Repair ◽  
Therapeutic Potential ◽  
Vascular Endothelial ◽  
Glial Derived Neurotrophic Factor ◽  
Transcriptomic Changes ◽  
Endothelial Growth Factor ◽  
Cellular Components ◽  
Hepatocyte Growth ◽  
Go Terms

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome. Conditioning MSC with macrophage-derived inflammation resulted in 3208 differentially expressed genes, which were annotated with significantly enriched GO terms for 1085 biological processes, 85 cellular components, and 79 molecular functions. Inflammation-mediated conditioning increased the secretion of growth factors that are key for tissue repair, including vascular endothelial growth factor, hepatocyte growth factor, nerve growth factor and glial-derived neurotrophic factor. Furthermore, we found that inflammation-mediated conditioning induces transcriptomic changes that challenge the viability and mobility of MSC. Our data support the notion that macrophage-derived inflammation stimulates MSC to augment their paracrine repair-supporting activity. The results suggest that inflammatory pre-conditioning enhances the therapeutic potential of MSC transplants.

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.

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