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Sample records for ablation links vegf

  1. VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy

    Cao, Renhai; Xue, Yuan; Hedlund, Eva-Maria;

    2010-01-01

    , and adenoviral vectors ablates pericytes from the mature retinal vasculature through the VEGF receptor 1 (VEGFR1)-mediated signaling pathway, leading to increased vascular leakage. In contrast, we demonstrate VEGF receptor 2 (VEGFR2) is primarily expressed in nonvascular photoreceptors and ganglion cells...

  2. Selective Life-Long Skeletal Myofiber-Targeted VEGF Gene Ablation Impairs Exercise Capacity in Adult Mice.

    Tang, Kechun; Gu, Yusu; Dalton, Nancy D; Wagner, Harrieth; Peterson, Kirk L; Wagner, Peter D; Breen, Ellen C

    2016-02-01

    Exercise is dependent on adequate oxygen supply for mitochondrial respiration in both cardiac and locomotor muscle. To determine whether skeletal myofiber VEGF is critical for regulating exercise capacity, independent of VEGF function in the heart, ablation of the VEGF gene was targeted to skeletal myofibers (skmVEGF-/-) during embryogenesis (∼ E9.5), leaving intact VEGF expression by all other cells in muscle. In adult mice, VEGF levels were decreased in the soleus (by 65%), plantaris (94%), gastrocnemius (74%), EDL (99%) and diaphragm (64%) (P exercise capacity. PMID:26201683

  3. The enhancement of VEGF-mediated angiogenesis by polycaprolactone scaffolds with surface cross-linked heparin

    Singh, Shivani; Wu, Benjamin M.; Dunn, James C.Y.

    2010-01-01

    This study investigates the effect of surface cross-linked heparin on vascular endothelial growth factor (VEGF)-mediated angiogenesis in porous polycaprolactone (PCL) scaffolds in vivo. We tested the hypothesis that VEGF delivered by scaffolds coated with a sub-micron thick layer of immobilized heparin would accelerate angiogenesis. The bioactivity of retained VEGF was confirmed by its phosphorylation of VEGF receptor-2. After 7 and 14 days of subcutaneous implantation in mice, the heparin-PC...

  4. The Vascular-Ablative Agent VEGF121/rGel Inhibits Pulmonary Metastases of MDA-MB-231 Breast Tumors

    Sophia Ran

    2005-05-01

    Full Text Available VEGF121/rGel, a fusion protein composed of the growth factor VEGF121 and the recombinant toxin gelonin (rGel, targets the tumor neovasculature and exerts impressive cytotoxic effects by inhibiting protein synthesis. We evaluated the effect of VEGF121/rGel on the growth of metastatic MDA-MB-231 tumor cells in SCID mice. VEGF121/rGel treatment reduced surface lung tumor foci by 58% compared to controls (means were 22.4 and 53.3, respectively; P < .05 and the mean area of lung colonies by 50% (210 ± 37 m2vs 415 ± 10 m2 for VEGF121/rGel and control, respectively; P < .01. In addition, the vascularity of metastatic foci was significantly reduced: (198 ± 37 vs 388 ± 21 vessels/mm2 for treated and control, respectively. Approximately 62% of metastatic colonies from the VEGF121/rGel-treated group had fewer than 10 vessels per colony compared to 23% in the control group. The VEGF receptor Flk-1 was intensely detected on the metastatic vessels in the control but not in the VEGF121/rGel-treated group. Metastatic foci present in lungs had a three-fold lower Ki-67 labeling index compared to control tumors. Thus, the antitumor vascular-ablative effect of VEGF121/rGel may be utilized not only for treating primary tumors but also for inhibiting metastatic spread and vascularization of metastases.

  5. VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme.

    Debinski, W; Slagle-Webb, B.; Achen, M. G.; Stacker, S A; Tulchinsky, E; Gillespie, G. Y.; Gibo, D. M.

    2001-01-01

    BACKGROUND: Glioblastoma multiforme (GBM) is a hypervascularized and locally infiltrating brain tumor of astroglial origin with a very poor prognosis. An X-linked c-fos oncogene-inducible mitogenic, morphogenic, and angiogenic factor, endothelial growth factor-D (VEGF-D), is the newest mammalian member of VEGF family. We analyzed VEGF-D in GBM because of its high angiogenic potential and its linkage to the X chromosome. MATERIALS AND METHODS: Nonmalignant brain and GBM tissue sections as well...

  6. Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity

    Kurtagic, Elma; Jedrychowski, Mark P.; Nugent, Matthew A.

    2009-01-01

    Excessive neutrophil elastase (NE) activity and altered vascular endothelial growth factor (VEGF) signaling have independently been implicated in the development and progression of pulmonary emphysema. In the present study, we investigated the potential link between NE and VEGF. We noted that VEGF165 is a substrate for NE. Digestion of purified VEGF165 with NE generated a partially degraded disulfide-linked fragment of VEGF. Mass spectrometric analysis revealed that NE likely cleaves VEGF165 ...

  7. Adipose VEGF Links the White-to-Brown Fat Switch With Environmental, Genetic, and Pharmacological Stimuli in Male Mice.

    During, Matthew J; Liu, Xianglan; Huang, Wei; Magee, Daniel; Slater, Andrew; McMurphy, Travis; Wang, Chuansong; Cao, Lei

    2015-06-01

    Living in an enriched environment (EE) decreases adiposity, increases energy expenditure, causes resistance to diet induced obesity, and induces brown-like (beige) cells in white fat via activating a hypothalamic-adipocyte axis. Here we report that EE stimulated vascular endothelial growth factor (VEGF) expression in a fat depot-specific manner prior to the emergence of beige cells. The VEGF up-regulation was independent of hypoxia but required intact sympathetic tone to the adipose tissue. Targeted adipose overexpression of VEGF reproduced the browning effect of EE. Adipose-specific VEGF knockout or pharmacological VEGF blockade with antibodies abolished the induction of beige cell by EE. Hypothalamic brain-derived neurotrophic factor stimulated by EE regulated the adipose VEGF expression, and VEGF signaling was essential to the hypothalamic brain-derived neurotrophic factor-induced white adipose tissue browning. Furthermore, VEGF signaling was essential to the beige cells induction by exercise, a β3-adrenergic agonist, and a peroxisome proliferator-activated receptor-γ ligand, suggesting a common downstream pathway integrating diverse upstream mechanisms. Exploiting this pathway may offer potential therapeutic interventions to obesity and metabolic diseases. PMID:25763639

  8. Laser-induced corneal cross-linking upon photorefractive ablation with riboflavin

    Kornilovskiy IM

    2016-04-01

    Full Text Available Igor M Kornilovskiy,1 Elmar M Kasimov,2 Ayten I Sultanova,2 Alexander A Burtsev1 1Department of Eye Diseases, Federal State Budgetary Institution “National Pirogov Medical Surgical Centre”, Ministry of Health, Moscow, Russia; 2Department of Eye Diseases, Zarifa Aliyeva National Ophthalmology Center, Ministry of Health, Baku, Azerbaijan Aim: To estimate the biomechanical effect of the laser-induced cross-linking resulting from photorefractive ablation of the cornea with riboflavin.Methods: Excimer laser ablation studies were performed ex vivo (32 eyes of 16 rabbits by phototherapeutic keratectomy (PTK and in vivo (24 eyes of 12 rabbits by transepithelial photorefractive keratectomy (TransPRK, with and without riboflavin saturation of the stroma. Then, we performed corneal optical coherence tomography on 36 eyes of 18 patients with varying degrees of myopia at different times after the TransPRK was performed with riboflavin saturation of the stroma.Results: Biomechanical testing of corneal samples saturated with riboflavin revealed cross-linking effect accompanied by the increase in tensile strength and maximum strength. PTK showed increase in tensile strength from 5.1±1.4 to 7.2±1.6 MPa (P=0.001, while TransPRK showed increase in tensile strength from 8.8±0.9 to 12.8±1.3 MPa (P=0.0004. Maximum strength increased from 8.7±2.5 to 12.0±2.8 N (P=0.005 in PTK and from 12.8±1.6 to 18.3±1.2 N (P=0.0004 in TransPRK. Clinical optical coherence tomography studies of the biomicroscopic transparent cornea at different times after TransPRK showed increased density in the surface layers of the stroma and membrane-like structure beneath the epithelium.Conclusion: Photorefractive ablation of the preliminary corneal stroma saturation with riboflavin causes the effect of laser-induced cross-linking, which is attended with an increase in corneal tensile strength, maximum strength, increased density in the surface layers of the stroma, and formation of

  9. Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells

    Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. - Graphical abstract: Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells. Brief summary In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. - Highlights: • The anti-angiogenic effect and the mechanistic action of α-TEA were investigated. • α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo. • α-TEA down

  10. Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells

    Chuang, Cheng-Hung, E-mail: chchuang@hk.edu.tw [Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, 1018 Sec. 6 Taiwan Boulevard, Taichung 43302, Taiwan, ROC (China); Liu, Chia-Hua [Department of Food Science and Biotechnology, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China); Lu, Ta-Jung [Department of Chemistry, Institute of Technology and Innovation Management, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China); Hu, Miao-Lin, E-mail: mlhuhu@dragon.nchu.edu.tw [Department of Food Science and Biotechnology, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China)

    2014-12-15

    Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. - Graphical abstract: Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells. Brief summary In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. - Highlights: • The anti-angiogenic effect and the mechanistic action of α-TEA were investigated. • α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo. • α-TEA down

  11. Endometrial ablation

    Hysteroscopy-endometrial ablation; Laser thermal ablation; Endometrial ablation-radiofrequency; Endometrial ablation-thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ablation

  12. Miniaturizing VEGF: Peptides mimicking the discontinuous VEGF receptor-binding site modulate the angiogenic response

    De Rosa, Lucia; Finetti, Federica; Diana, Donatella; di Stasi, Rossella; Auriemma, Sara; Romanelli, Alessandra; Fattorusso, Roberto; Ziche, Marina; Morbidelli, Lucia; D’Andrea, Luca Domenico

    2016-08-01

    The angiogenic properties of VEGF are mediated through the binding of VEGF to its receptor VEGFR2. The VEGF/VEGFR interface is constituted by a discontinuous binding region distributed on both VEGF monomers. We attempted to reproduce this discontinuous binding site by covalently linking into a single molecular entity two VEGF segments involved in receptor recognition. We designed and synthesized by chemical ligation a set of peptides differing in length and flexibility of the molecular linker joining the two VEGF segments. The biological activity of the peptides was characterized in vitro and in vivo showing a VEGF-like activity. The most biologically active mini-VEGF was further analyzed by NMR to determine the atomic details of its interaction with the receptor.

  13. VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase

    Wright, Gary L.; Maroulakou, Ioanna G.; Eldridge, Juanita; Liby, Tiera L.; Sridharan, Vijayalakshmi; Tsichlis, Philip N.; Muise-Helmericks, Robin C.

    2008-01-01

    The growth factor, vascular endothelial growth factor (VEGF), induces angiogenesis and promotes endothelial cell (EC) proliferation. Affymetrix gene array analyses show that VEGF stimulates the expression of a cluster of nuclear-encoded mitochondrial genes, suggesting a role for VEGF in the regulation of mitochondrial biogenesis. We show that the serine threonine kinase Akt3 specifically links VEGF to mitochondrial biogenesis. A direct comparison of Akt1 vs. Akt3 gene silencing was performed ...

  14. Therapeutic action of the mitochondria-targeted antioxidant SkQ1 on retinopathy in OXYS rats linked with improvement of VEGF and PEDF gene expression.

    Anton M Markovets

    Full Text Available UNLABELLED: The incidence of age-related macular degeneration (AMD, the main cause of blindness in older patients in the developed countries, is increasing with the ageing population. At present there is no effective treatment for the prevailing geographic atrophy, dry AMD, whereas antiangiogenic therapies successful used in managing the wet form of AMD. Recently we showed that mitochondria-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1 is able to prevent the development and moreover caused regression of pre-existing signs of the retinopathy in OXYS rats, an animal model of AMD. Here we examine the effects of SkQ1 on expression of key regulators of angiogenesis vascular endothelial growth factor A (VEGF and its antagonist pigment epithelium-derived factor (PEDF genes in the retina of OXYS rats as evidenced by real-time PCR and an ELISA test for VEGF using Wistar rats as control. Ophthalmoscopic examinations confirmed that SkQ1 supplementation (from 1.5 to 3 months of age, 250 nmol/kg prevented development while eye drops SkQ1 (250 nM, from 9 to 12 months caused some reduction of retinopathy signs in OXYS rats and did not reveal any negative effects on the control Wistar rat's retina. Prevention of premature retinopathy by SkQ1 was connected with an increase of VEGF mRNA and protein in OXYS rat's retina up to the levels corresponding to the Wistar rats, and did not involve changes in PEDF expression. In contrast the treatment with SkQ1 drops caused a decrease of VEGF mRNA and protein levels and an increase in the PEDF mRNA level in the middle-aged OXYS rats, but in Wistar rats the changes of gene expression were the opposite. CONCLUSIONS: The beneficial effects of SkQ1 on retinopathy connected with normalization of expression of VEGF and PEDF in the retina of OXYS rats and depended on age of the animals and the stage of retinopathy.

  15. VEGF and radiation sensibility

    VEGF (vascular endothelial growth factor) is important for tumor growth, local invasion and the distant metastasis. It provides important information about the biology and the clinical behavior of tumors undergoing radiotherapy. This review summarizes the present study reports and suggests: (1) Irradiation can induce VEGF expression in diverse tumor cell types. (2) VEGF can be as a predictive factor of response to radiotherapy. VEGF increase in tumors will be resistant to radiation therapy. Anti-VEGF strategies can be used in combination with radiation therapy, and it can increase the anti-tumor effects of radiation therapy. A classification of tumors according to their VEGF level before therapy can be used into designed individual treatment planning

  16. SIGNIFICANCE OF INSPECTING SERUM VEGF DURING THERAPY OF TUMOR

    薛文成; 孟冬娅; 杨婧; 罗军

    2002-01-01

    Objective: To investigate the clinical significance of the serum VEGF as amarker for monitoring the clinical course of tumor patients cured by surgery and radiotherapy. Methods: Enzyme linked immunosobent assay (ELISA) was used to detect serum levels of VEGF in the patients with carcinoma. Results: X-ray irradiation could induce the tumor cells to express and secret VEGF. Patients with elevated values of serum VEGF 60 days after radiotherapy had higher rate of tumor recurrence and metastasis. There was more chance of metastasis in lung cancer patients with higher level of VEGF after surgical resection (12/21). Less post-operation (3 months~4 years) patients without relapse or cancerometastasis showed elevated values of serum VEGF than those with relapse or cancerometastasis. There was negative correlation between the serum Hb and VEGF in the tumor patients (( =-0.289, P<0.01). In the 28 patients with normal Hb levels at pre-operation, 17 patients with decreased Hb levels had more chance getting higher VEGF after operation than the others (P<0.05). Conclusion: clinical manifestation should be considered in the application of serum VEGF as a tumor marker, a prognostic factor,and a recurrence indicator of tumor. To determine the levels of serum VEGF and Hb, correct the low level of Hb and block the effect of VEGF by special means may be helpful for tumor patients.

  17. A role for VEGF as a negative regulator of pericyte function and vessel maturation.

    Greenberg, Joshua I; Shields, David J; Barillas, Samuel G; Acevedo, Lisette M; Murphy, Eric; Huang, Jianhua; Scheppke, Lea; Stockmann, Christian; Johnson, Randall S; Angle, Niren; Cheresh, David A

    2008-12-11

    Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) through their cognate receptors on endothelial cells and vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. Although VEGF directly stimulates endothelial cell proliferation and migration, its role in pericyte biology is less clear. Here we define a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rbeta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rbeta and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumour cell VEGF disrupts PDGF-Rbeta/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signalling as both a promoter of endothelial cell function and a negative regulator of VSMCs and vessel maturation. PMID:18997771

  18. VEGF involvement in psoriasis

    Mihaela Elena Marina

    2015-07-01

    Full Text Available Vascular endothelial growth factor (VEGF is a key growth factor, regulating the neovascularization, during embryogenesis, skeletal growth, reproductive functions and pathological processes. The VEGF receptors (VEGFR are present in endothelial cells and other cell types, such as vascular smooth muscle cells, hematopoietic stem cells, monocytes, neurons, macrophages, and platelets.Angiogenesis is initiated by the activation of vascular endothelial cells through several factors. The excess dermal vascularity and VEGF production are markers of psoriasis.The pathological role of VEGF/VEGFR signaling during the psoriasis onset and evolution makes it a promising target for the treatment of psoriasis. Antibodies and other types of molecules targeting the VEGF pathway are currently evaluated in arresting the evolution of psoriasis.

  19. VEGF involvement in psoriasis.

    Marina, Mihaela Elena; Roman, Iulia Ioana; Constantin, Anne-Marie; Mihu, Carmen Mihaela; Tătaru, Alexandru Dumitru

    2015-01-01

    Vascular endothelial growth factor (VEGF) is a key growth factor, regulating the neovascularization, during embryogenesis, skeletal growth, reproductive functions and pathological processes. The VEGF receptors (VEGFR) are present in endothelial cells and other cell types, such as vascular smooth muscle cells, hematopoietic stem cells, monocytes, neurons, macrophages, and platelets. Angiogenesis is initiated by the activation of vascular endothelial cells through several factors. The excess dermal vascularity and VEGF production are markers of psoriasis. The pathological role of VEGF/VEGFR signaling during the psoriasis onset and evolution makes it a promising target for the treatment of psoriasis. Antibodies and other types of molecules targeting the VEGF pathway are currently evaluated in arresting the evolution of psoriasis. PMID:26609252

  20. VEGF involvement in psoriasis

    MARINA, MIHAELA ELENA; ROMAN, IULIA IOANA; CONSTANTIN, ANNE-MARIE; Carmen Mihaela MIHU; TĂTARU, ALEXANDRU DUMITRU

    2015-01-01

    Vascular endothelial growth factor (VEGF) is a key growth factor, regulating the neovascularization, during embryogenesis, skeletal growth, reproductive functions and pathological processes. The VEGF receptors (VEGFR) are present in endothelial cells and other cell types, such as vascular smooth muscle cells, hematopoietic stem cells, monocytes, neurons, macrophages, and platelets. Angiogenesis is initiated by the activation of vascular endothelial cells through several factors. The excess de...

  1. Relationship between Expression of beta-catenin and VEGFs(VEGFA,VEGF-C),VEGF Receptors-2(VEGFR-2)in Medulloblastoma

    ZHANG Hong-mei; ZHANG Xiong; LI Yu; MI Can

    2008-01-01

    Objective:To investigate the expression of beta-catenin and VEGFs(VEGF-A,VEGF-C)and VEGF receptor-2(VEGFR-2)protein in medulloblastoma.Methods:Immunohistochemical staining with SP method Was conducted to determine the expression of beta-eatenin and VEGFs(VEGF-A,VEGF-C)and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results:The expression rate of beta-catenin,and VEGFs (VEGF-A,VEGF-C)and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue.A significant positive correlation was found between beta-catenin and VEGFs(VEGF-A,VEGF-C)and VEGFR-2 protein in medulloblastoma. Conclusion:There was a correlation between beta-catenin and VEGFs(VEGF-A,VEGF-C)and VEGFR-2 in medulloblastoma,which may play a role in the pathogenesis and development of medulloblastoma.

  2. Elevated IGFIR expression regulating VEGF and VEGF-C predicts lymph node metastasis in human colorectal cancer

    Insulin-like growth factor-I receptor (IGFIR) has been shown to regulate the tumor development. The objective of the current study is to determine the association of IGFIR with lymph node metastasis and to explore the related mechanism in human colorectal cancer in clinic. In a random series of 98 colorectal cancer patients, the expressions of IGFIR, vascular endothelial growth factor (VEGF) and VEGF-C were investigated by immunohistochemistry, and the association of these expressions with lymph node metastasis was statistically analyzed. The expressions of VEGF and VEGF-C in colorectal cancer cells stimulated with IGF-I were also examined by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Higher rates of IGFIR (46%), VEGF (53%), and VEGF-C (46%) expression were found in colorectal cancer tissues than in normal and colorectal adenoma tissues. These expressions were significantly associated with clinicopathologic factors and lymph node status. We also found the concomitant high expressions of IGFIR/VEGF (P < 0.001) and IGFIR/VEGF-C (P = 0.001) had a stronger correlation with lymph node metastasis than did each alone or both low expressions. In addition, IGF-I could effectively induce the VEGF and VEGF-C mRNA expression and protein secretion in colorectal cancer cells expressing IGFIR molecules. Moreover, Patients who had strong staining for IGFIR, VEGF and VEGF-C showed significantly less favorable survival rates compared with patients who had low staining for these molecules (P < 0.001). The survival rates of patients who were both high expression of IGFIR/VEGF and IGFIR/VEGF-C also were significantly lower compared with patients who were negative or one of high expression of these molecules (P < 0.001). Together the findings indicated for the first time that simultaneous examination of the expressions of IGFIR, VEGF and VEGF-C will benefit the diagnosis of lymph node metastasis in order to assay the

  3. Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells

    Timoshenko, A V; Rastogi, S; Lala, P K

    2007-01-01

    Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin α9β1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231, Hs578T, SK-BR-3, T-47D, and MCF7) and their possible requirement in migration of two VEGF-C-secreting, highly metastatic lines MDA-MB-231 and Hs578T. While cell lines varied significantly in their expression of above VEGF-C receptors, migratory activity of MDA-MB-231 and Hs578T cells was linked to one or more of these receptors. Depletion of endogenous VEGF-C by treatments with a neutralising antibody, VEGF-C siRNA or inhibitors of Src, EGFR/Her2/neu and p38 MAP kinases which inhibited VEGF-C production, inhibited cellular migration, indicating the requirement of VEGF-C for migratory function. Migration was differentially attenuated by blocking or downregulation of different VEGF-C receptors, for example treatment with a VEGFR-2 tyrosine kinase inhibitor, NRP-1 and NRP-2 siRNA or α9β1 integrin antibody, indicating the participation of one or more of the receptors in cell motility. This novel role of tumour-derived VEGF-C indicates that breast cancer metastasis can be promoted by coordinated stimulation of lymphangiogenesis and enhanced migratory activity of breast cancer cells. PMID:17912247

  4. Low-weight polyethylenimine cross-linked 2-hydroxypopyl-ß-cyclodextrin and folic acid as an efficient and nontoxic siRNA carrier for gene silencing and tumor inhibition by VEGF siRNA

    Li JM

    2013-06-01

    Full Text Available Jin-Ming Li, Yuan-Yuan Wang, Wei Zhang, Hua Su, Liang-Nian Ji, Zong-Wan Mao MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, People's Republic of China Background: Targeted delivery of small interfering RNA (siRNA has been regarded as one of the most important technologies for the development of siRNA therapeutics. However, the need for safe and efficient delivery systems is a barrier to further development of RNA interference therapeutics. In this work, a nontoxic and efficient siRNA carrier delivery system of low molecular weight polyethyleneimine (PEI-600 Da cross-linked with 2-hydroxypopyl-β-cyclodextrin (HP-β-CD and folic acid (FA was synthesized for biomedical application. Methods: The siRNA carrier was prepared using a simple method and characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. The siRNA carrier nanoparticles were characterized in terms of morphology, size and zeta potential, stability, efficiency of delivery, and gene silencing efficiency in vitro and in vivo. Results: The siRNA carrier was synthesized successfully. It showed good siRNA binding capacity and ability to protect siRNA. Further, the toxicity of the carrier measured in vitro and in vivo appeared to be negligible, probably because of degradation of the low molecular weight PEI and HP-β-CD in the cytosol. Flow cytometry and confocal microscopy confirmed that the FA receptor-mediated endocytosis of the FA-HP-β-CD-PEI/siRNA complexes was greater than that of the HP-β-CD-PEI/siRNA complexes in FA receptor-enriched HeLa cells. The FA-HP-β-CD-PEI/siRNA complexes also demonstrated excellent gene silencing efficiency in vitro (in the range of 90%, and reduced vascular endothelial growth factor (VEGF protein expression in the presence of 20% serum. FA-HP-β-CD-PEI/siRNA complexes administered via tail vein injection resulted in marked

  5. Preparation and Characterization of RGDS/Nanodiamond as a Vector for VEGF-siRNA Delivery.

    Cui, Chunying; Wang, Yuji; Yang, Kaikai; Wang, Yaonan; Yang, Junyu; Xi, Jianzhong; Zhao, Ming; Wu, Jianhui; Peng, Shiqi

    2015-01-01

    Small interfering RNA (siRNA) has great potential for treating or preventing diseases. Safe and efficient vectors are extremely needed for specific delivery of siRNA. Here VEGF-siRNA/RGDS/nanodiamond was prepared by conjugating Arg-Gly-Asp-Ser (RGDS) and VEGF-siRNA to nanodiamond delivery particles. VEGF-siRNA could be clinically used in anti-angiogenic gene therapy to inhibit tumor growth via the down-regulation of the expression of vascular endothelial growth factor (VEGF). The differential scanning calorimeter (DSC) analysis evidenced that RGDS and/or VEGF-siRNA were effectively linked to nanodiamond. The release assays indicated that in the presence of RGDS the release time of VEGF-siRNA was prolonged by 6 folds. This enabled VEGF-siRNA/RGDS/nanodiamond to release and transfer VEGF-siRNA in a long-acting manner, and thereby to significantly decrease the expression of VEGF mRNA and protein. Real-Time PCR analysis revealed that the expression of VEGF mRNA was decreased 87.56 ± 1.6% by VEGF-siRNA/RGDS/nanodiamond. Enzyme-Linked Immunosorbent Assay (ELISA) indicated that the expression of VEGF protein was down-regulated to 39.8 ± 1.8%. The down-regulation of VEGF protein expression was also observed in Western blotting experiments. In human umbilical vein endothelial cells (HUVEC) test, VEGF-siRNA/RGDS/nanodiamond decreased the formation of the tubes and exhibited no testable cytotoxicty. All the results consistently suggested that RGDS/nanodiamond is an ideal non-viral tumor-targeting vector for siRNA transfer, and VEGF-siRNA/RGDS/nanodiamond may be a promising regimen of gene therapy in carcinoma. PMID:26301301

  6. VEGF121b and VEGF165b are weakly angiogenic isoforms of VEGF-A

    Pio Ruben

    2010-12-01

    Full Text Available Abstract Background Different isoforms of VEGF-A (mainly VEGF121, VEGF165 and VEGF189 have been shown to display particular angiogenic properties in the generation of a functional tumor vasculature. Recently, a novel class of VEGF-A isoforms, designated as VEGFxxxb, generated through alternative splicing, have been described. Previous studies have suggested that these isoforms may inhibit angiogenesis. In the present work we have produced recombinant VEGF121/165b proteins in the yeast Pichia pastoris and constructed vectors to overexpress these isoforms and assess their angiogenic potential. Results Recombinant VEGF121/165b proteins generated either in yeasts or mammalian cells activated VEGFR2 and its downstream effector ERK1/2, although to a lesser extent than VEGF165. Furthermore, treatment of endothelial cells with VEGF121/165b increased cell proliferation compared to untreated cells, although such stimulation was lower than that induced by VEGF165. Moreover, in vivo angiogenesis assays confirmed angiogenesis stimulation by VEGF121/165b isoforms. A549 and PC-3 cells overexpressing VEGF121b or VEGF165b (or carrying the PCDNA3.1 empty vector, as control and xenotransplanted into nude mice showed increased tumor volume and angiogenesis compared to controls. To assess whether the VEGFxxxb isoforms are differentially expressed in tumors compared to healthy tissues, immunohistochemical analysis was conducted on a breast cancer tissue microarray. A significant increase (p xxxb and total VEGF-A protein expression in infiltrating ductal carcinomas compared to normal breasts was observed. A positive significant correlation (r = 0.404, p = 0.033 between VEGFxxxb and total VEGF-A was found. Conclusions Our results demonstrate that VEGF121/165b are not anti-angiogenic, but weakly angiogenic isoforms of VEGF-A. In addition, VEGFxxxb isoforms are up-regulated in breast cancer in comparison with non malignant breast tissues. These results are to be taken

  7. VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

    Gareth W. Fearnley

    2016-05-01

    Full Text Available Vascular endothelial growth factor A (VEGF-A binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145 promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.

  8. Regulating VEGF signaling in platelet concentrates via specific VEGF sequestering.

    Belair, David G; Le, Ngoc Nhi; Murphy, William L

    2016-05-26

    Platelets contain an abundance of growth factors that mimic the composition of the wound healing milieu, and platelet-derived VEGF in particular can negatively influence wound healing if unregulated. Here, we sought to capture and regulate the activity of VEGF factor from human platelets using poly(ethylene glycol) microspheres. In this communication, we demonstrate that platelet freeze/thaw produced significantly higher levels of Vascular Endothelial Growth Factor (VEGF) than either calcium chloride treatment, protease activated receptor 1 activating peptide (PAR1AP) treatment, or thrombin treatment. PEG microspheres containing a VEGF-binding peptide (VBP), derived from VEGFR2, sequestered VEGF from platelet concentrate, prepared via freeze/thaw, and reduced the bioactivity of platelet concentrate in HUVEC culture, which suggests that VBP microspheres sequestered and reduced the activity of VEGF from patient-derived platelets. Here, we demonstrate the ability of VEGF sequestering microspheres to regulate the activity of VEGF derived from a growth factor-rich autologous human blood product. PMID:27010034

  9. CXCL7-Mediated Stimulation of Lymphangiogenic Factors VEGF-C, VEGF-D in Human Breast Cancer Cells

    Minghuan Yu

    2010-01-01

    Full Text Available Increased expression of lymphangiogenesis factors VEGF-C/D and heparanase has been correlated with the invasion of cancer. Furthermore, chemokines may modify matrix to facilitate metastasis, and they are associated with VEGF-C and heparanase. The chemokine CXCL7 binds heparin and the G-protein-linked receptor CXCR2. We investigated the effect of CXCR2 blockade on the expression of VEGF-C/D, heparanase, and on invasion. CXCL7 siRNA and a specific antagonist of CXCR2 (SB225002 were used to treat CXCL7 stably transfected MCF10AT cells. Matrigel invasion assays were performed. VEGF-C/D expression and secretion were determined by real-time PCR and ELISA assay, and heparanase activity was quantified by ELISA. SB225002 blocked VEGF-C/D expression and secretion (P<.01. CXCL7 siRNA knockdown decreased heparanase (P<.01. Both SB225002 and CXCL7 siRNA reduced the Matrigel invasion (P<.01. The MAP kinase signaling pathway was not involved. The CXCL7/CXCR2 axis is important for cell invasion and the expression of VEGF-C/D and heparanase, all linked to invasion.

  10. Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice.

    Knapp, Amy E; Goldberg, Daniel; Delavar, Hamid; Trisko, Breanna M; Tang, Kechun; Hogan, Michael C; Wagner, Peter D; Breen, Ellen C

    2016-07-01

    A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P < 0.05) and endurance capacity (-47%; P < 0.05), which did not persist after 8 wk. In skmVEGF-/- mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity. PMID:27225953

  11. VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab

    2008-01-01

    AIM: To gain mechanistic insights into the role played by epidermal growth factor receptor (EGFR) in the reg- ulation of vascular endothelial growth factors (VEGFs) in colorectal cancer (CRC). METHODS: The impact of high-level expression of the growth factor receptors EGFR and VEGF recep- tor (VEGFR)3 and the VEGFR3 ligands VEGF-C and VEGF-D on disease progression and prognosis in hu- man CRC was investigated in 108 patients using immu- nohistochemistry. Furthermore, the expression of the lymphangiogenic factors in response to the modulation of EGFR signalling by the EGFR-targeted monoclonal antibody cetuximab was investigated at the mRNA and protein level in human SW480 and SW620 CRC cell lines and a mouse xenograft model. RESULTS: Human CRC specimens and cell lines dis- played EGFR, VEGF-C and VEGF-D expression with varying intensities. VEGF-C expression was associated with histological grade. Strong expression of VEGF-D was significantly associated with lymph node metas- tases and linked to a trend for decreased survival in lymph node-positive patients. EGFR blockade with ce- tuximab resulted in a significant decrease of VEGF-D expression in vitro and in vivo. CONCLUSION: In conclusion, the expression of VEGF-D in colorectal tumours is significantly associated with lymphatic involvement in CRC patients and such expression might be blocked effectively by cetuximab.

  12. VEGF Inhibitors for Cancer Therapy

    Prakash S. Sukhramani

    2010-01-01

    Full Text Available Despite significant advances in systemic therapies, radiation oncology, and surgical techniques, many patients with cancer are still incurable. A novel therapeutic approach has been to target the vascular endothelial growth factors (VEGFs which are often mutated and/or over-expressed in many tumors. The ligands and receptors of VEGF family are well established as key regulators of angiogenesis and vasculogenesis processes. VEGF is a homodimeric, basic, 45 kDa glycoprotein specific for vascular endothelial cells. Specifically, VEGF participates in regulation of the female reproductive cycle, wound healing, inflammation, vascular permeability, vascular tone, hematopoiesis and also contributes to pathological angiogenesis disorders such as cancer, rheumatoid arthritis, diabetic retinopathy and the neovascular form of macular degeneration. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Clinical trials have anti-VEGF therapies are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. The aim of present review is on the cellular responses of VEGF inhibitors and their implications for cancer therapy.

  13. AlphaB-crystallin is involved in oxidative stress protection determined by VEGF in skeletal myoblasts.

    Mercatelli, Neri; Dimauro, Ivan; Ciafré, Silvia Anna; Farace, Maria Giulia; Caporossi, Daniela

    2010-08-01

    Recent studies suggest that the effects of VEGF-A, the prototype VEGF ligand, may extend to a variety of cell types other than endothelial cells. The expression of VEGF-A and its main receptors, Flt-1/VEGFR-1 and KDR/Flk-1/VEGFR-2, was indeed detected in several cell types, including cardiac myocytes and regenerating myotubes. In addition to its proangiogenic activity, evidence indicates that VEGF-A can sustain skeletal muscle regeneration by enhancing the survival and migration of myogenic cells and by promoting the growth of myogenic fibers. In this study, our aim was to investigate whether VEGF could protect skeletal muscle satellite cells from apoptotic cell death triggered by reactive oxygen species and to identify the main molecular mechanisms. C2C12 mouse myoblasts, cultured in vitro in the presence of exogenous VEGF or stably transfected with a plasmid vector expressing VEGF-A, were subjected to oxidative stress and analyzed for cell growth and survival, induction of apoptosis, and molecular signaling. The results of our study demonstrated that VEGF protects C2C12 myoblasts from apoptosis induced by oxidative or hypoxic-like stress. This protection did not correlate with the modulation of the expression of VEGF receptors, but is clearly linked to the phosphorylation of the KDR/Flk-1 receptor, the activation of NF-kappaB, and/or the overexpression of the antiapoptotic protein alphaB-crystallin. PMID:20441791

  14. VEGF expression and FDG kinetics

    Aim: The kinetics of dynamic PET FDG studies in musculoskeletal tumors was compared with the quantitative measurements of VEGF expression. Methods: Dynamic PET FDG studies were performed in 35 patients with sarcomas prior to surgery. The PET data were acquired for 60 minutes using a dedicated PET ring system. Following iterative image reconstruction, the data were quantified using a dedicated software program. Besides the calculation of SUV, a two compartment model was used to retrieve the parameters VB (vessel density) and the FDG transport constants K1-k4. Furthermore, a non-compartment model was applied to gain information about the tumor heterogeneity using the fractal dimension (FD). Following surgery, tissue samples were processed by quantitative RT-PCR using a lightcycler system for VEGF, the vascular endothelial growth factor, important for the tumor angiogenesis. Results: Scatter plots demonstrate, that the VEGF expression was generally associated with higher K1 values. The vessel density was independent from the VEGF expression. While the VEGF expression was variable at low SUV, the expression of VEGF was generally increased when the SUV exceeded 4.0. The simple linear correlation analysis of the parameters provided no significant correlations. A multi-factorial regression function was calculated, using SUV, K1-k4, VB and FD as predictor variables and the measured VEGF expression as the target variable. We noted a correlation of r=0.88 for these parameters, demonstrating that the dynamic of FDG accumulation is associated with angiogenetic activity. Conclusion: The results demonstrate, that tumor angiogenesis modulate the kinetics of FDG accumulation

  15. VEGFR2-Mediated Vascular Dilation as a Mechanism of VEGF-Induced Anemia and Bone Marrow Cell Mobilization

    Sharon Lim

    2014-10-01

    Full Text Available Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1TK−/− did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1+/VEGFR2+ populations in peripheral blood and BM showed no significant ratio difference between VEGF- and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy.

  16. VEGF-B: a thing of beauty

    Xuri Li

    2010-01-01

    More than a decade ago, when we first embarked on our journey to delineate the biological function of vascular endothelial growth factor B (VEGF-B),we had a hard time comprehending why VEGF-B was needed. In mice, geneticdeletion of VEGF-B seemed to be harmless, since the VEGF-B null mice, to a large extent, can still live a fairly normal life [1].

  17. Binding MR target contrast agent precursor-VEGF165- aptamer and VEGF165 in vitro%MR靶向对比剂前体——VEGF165-适配体与VEGF165体外结合实验研究

    尤晓光; 白玉杰; 涂蓉

    2011-01-01

    目的 应用酶联免疫吸附实验 (ELISA)检测MR靶向对比剂前体--血管内皮生长因子165-适配体(VEGF165-aptamer)与VEGF165的体外结合能力,以了解其对VEGF的靶向性.方法 实验组采用亲和素96孔酶标板, 包被生物素化VEGF165-aptamer, 设置递减的浓度梯度(共9组)和空白对照组,采用组间方差分析.结果 实验组包被生物素化VEGF165-aptamer浓度在50~0.78 pmol/ μL时,实验组与空白组及实验各相邻组间差异有统计学意义(P0.05).结论 采用ELISA检测技术验证了VEGF165-aptamer与VEGF165间的体外结合能力,其有效最低小包被浓度为0.78 pmol/ μL, VEGF165-aptamer对VEGF165有良好的靶向性.%Objective To investigate the binding ability of MR target contrast agent precursor-vascular endothelial growth factor 165 (VEGF165)-aptamer with VEGF165 in vitro using enzyme-linked immunosorbent assay method.Methods In the test groups, the biotinylation VEGF165-aptamer was coated onto the 96 well plates with gradient concentrations from 50 pmol/μL to 0.195 pmol/μL. The corresponding control groups were also set up. The data were analyzed with One-way ANOVA. The binding bern een VEGF165-aptamer and VEGF165 was identified with ELISA method.Results When the concentraion of VEGF165-aptamerwas at range of 50 pmol/μL~0.78 pmol/μl,,tbere was significant difference in binding between the experimental and control groups (P<0.05). When the concentration was at 0.39 pmol/μL and 0.195 pmol/μL, there was no significant difference in binding between two groups (P>0.05). Conclusion The minimal concentration of VEGF165-aptamer that can synthesize detectable binding is at 0.78 pmol/μL. The vascular endothelial growth factor 165-adaplation body has favorable target tropism to the WEGF165.

  18. Reinstate the Damaged VEGF Signaling Pathway with VEGF-activating Transcription Factor

    Yao-guo Yang; Heng Guan; Chang-wei Liu; Yong-jun Li

    2009-01-01

    Objective To investigate the role of vascular endothelial growth factor-activating transcriptional factor(VEGF-ATF)on the VEGF signaling pathway in diabetes mellitus.Methods Totally,20 C57BL/6 mice fed with high fat diet was induced into diabetes mellitus.Ten diabetes mellitus mice received a lower limb muscle injection with VEGF-ATF plasmid,and another ten were as control.VEGF-ATF is an engineered transcription factor designed to increase VEGF expression.Three days later,mice were sacrificed and the injected gastrocnemius was used for analysis.VEGF mRNA and protein expressions were examined by real-time PCR and ELISA respectively.VEGF receptor 2 mRNA expression was tested with RT-PCR.Phosphorylated Akt,Akt,endothelial nitric oxide synthase(eNOS),and phosphorylated eNOS were assessed by western blot.Results At 3 days post-injection,in mice with diabetes mellitus,VEGF gene transfer increased VEGF mRNA copies and VEGF protein expression in injected muscles compared with control;and reinstated the impaired VEGF signaling pathway with increasing the ratios of phosphorylated Akt/Akt and phosphorylated eNOS/eNOS.However,it did not affect the expression of VEGF receptor 2 mRNA.Conclusion Gene transfer with VEGF-ATF is able to reinstate the impaired VEGF downstream pathway,and potentially promote therapeutic angiogenesis in mice with diabetes mcllitus.

  19. Ablative and fractional ablative lasers.

    Brightman, Lori A; Brauer, Jeremy A; Anolik, Robert; Weiss, Elliot; Karen, Julie; Chapas, Anne; Hale, Elizabeth; Bernstein, Leonard; Geronemus, Roy G

    2009-10-01

    The field of nonsurgical laser resurfacing for aesthetic enhancement continues to improve with new research and technological advances. Since its beginnings in the 1980s, the laser-resurfacing industry has produced a multitude of devices employing ablative, nonablative, and fractional ablative technologies. The three approaches largely differ in their method of thermal damage, weighing degrees of efficacy, downtime, and side effect profiles against each other. Nonablative technologies generate some interest, although only for those patient populations seeking mild improvements. Fractional technologies, however, have gained dramatic ground on fully ablative resurfacing. Fractional laser resurfacing, while exhibiting results that fall just short of the ideal outcomes of fully ablative treatments, is an increasingly attractive alternative because of its far more favorable side effect profile, reduced recovery time, and significant clinical outcome. PMID:19850197

  20. Experimental study of treatment for radiation-damaged mice by transgenic VEGF

    Objective: To study the effect of VEGF gene expression in the treatment of radiation damage, and to explore its molecular mechanism by transferring eukaryotic expression plasmid containing VEGF gene into irradiated mice cells. Methods: Normally Kunming mice were divided randomly into three groups as control group, irradiated group and transferred VEGF gene group. The mice were administered with 8 Gy X-ray exposure after intramuscular injection of VEGF recombinant plasmid in the transgenic group. The animals were killed at different times after X-ray exposure. Their clinical manifestation, mortality rate, pathology of tissues and in situ apoptosis in thymus and splenic cells were observed. Results: VEGF165 gene fragments were amplified from pSP73/HVEGF165 plasmid by PCR method, and then linked with pcDNA3.1 vector after incision by double enzyme. The recombinant plasmid pcDNA3.1/VEGF165 was constructed. Electrophoresis and sequencing showed that the recombinant plasmid sequence was exactly the same with the data in GenBank. The mortality of irradiated group and transgenic group 14 d post-irradiation was 64% and 36%, respectively, with the statistical difference (t=3.92, P165 was successfully constructed. Transgenic treatment with recombinant plasmid can remarkably decrease the mortality and apoptosis rate of thymus and spleen cells in mice suffering from severe radiation damage, and improve the pathologic change of immune organs. VEGF transgenic technique is one of the effective methods for treating severe radiation injury. (authors)

  1. Serum VEGF and CFH in Exudative Age-Related Macular Degeneration

    Haas, Paulina; Steindl, Kerstin; Aggermann, Tina; Schmid-Kubista, Katharina; Krugluger, Walter; Hageman, Gregory S.; Binder, Susanne

    2014-01-01

    Purpose To determine serum vascular endothelial growth factor 165 (VEGF165) levels and the association of the complement factor H gene (CFH) Y402H polymorphism in patients with exudative age-related macular degeneration (AMD) in comparison to unaffected control subjects. Methods Sixty-six AMD patients and 66 healthy age- and gender-matched controls were included in this case-control study. The serum VEGF165 was assayed by ELISA (R&D). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Chisquared tests were used regarding the polymorphism, a t-test regarding the VEGF-levels. Results Levels of serum VEGF165 were similar in both groups (p-value = 0.2112). Genotype frequency differed significantly between patients with exudative AMD and the healthy control group (p = 0.003136). The serum VEGF165 levels were similar irrespective of the presence of the CFH Y402H polymorphism (p = 0.4113) and independent of the specific genotype (p = 0.9634). Conclusion In the present study exudative AMD is not associated to serum VEGF165 levels; furthermore, our data does not establish a statistical link between VEGF165 and the CFH Y402H polymorphism. PMID:21158586

  2. Mechanical Forces Induce Changes in VEGF and VEGFR-1/sFlt-1 Expression in Human Chondrocytes

    Rainer Beckmann

    2014-09-01

    Full Text Available Expression of the pro-angiogenic vascular endothelial growth factor (VEGF stimulates angiogenesis and correlates with the progression of osteoarthritis. Mechanical joint loading seems to contribute to this cartilage pathology. Cyclic equibiaxial strains of 1% to 16% for 12 h, respectively, induced expression of VEGF in human chondrocytes dose- and frequency-dependently. Stretch-mediated VEGF induction was more prominent in the human chondrocyte cell line C-28/I2 than in primary articular chondrocytes. Twelve hours of 8% stretch induced VEGF expression to 175% of unstrained controls for at least 24 h post stretching, in promoter reporter and enzyme-linked immunosorbent assay (ELISA studies. High affinity soluble VEGF-receptor, sVEGFR-1/sFlt-1 was less stretch-inducible than its ligand, VEGF-A, in these cells. ELISA assays demonstrated, for the first time, a stretch-mediated suppression of sVEGFR-1 secretion 24 h after stretching. Overall, strained chondrocytes activate their VEGF expression, but in contrast, strain appears to suppress the secretion of the major VEGF decoy receptor (sVEGFR-1/sFlt-1. The latter may deplete a biologically relevant feedback regulation to inhibit destructive angiogenesis in articular cartilage. Our data suggest that mechanical stretch can induce morphological changes in human chondrocytes in vitro. More importantly, it induces disturbed VEGF signaling, providing a molecular mechanism for a stress-induced increase in angiogenesis in cartilage pathologies.

  3. Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer

    Kut, C; Mac Gabhann, F.; Popel, A S

    2007-01-01

    Vascular endothelial growth factor (VEGF) is a major target for the inhibition of tumour vascularisation and the treatment of human cancer. Many tumours produce large quantities of VEGF, and as a result, diagnosis and prognosis of cancer may be predicted by measuring changes in VEGF concentrations in blood. In blood, the VEGF may be located in the plasma, or in the blood-borne cells and formed elements, in particular, platelets and leukocytes. In this study, we collate the measurements of VEG...

  4. Using Anti-VEGF in Diabetic Retinopathy

    Marashi, Ameen

    2016-01-01

    Vascular endothelium growth factor is the main pathological factor in diabetic retinopathy and diabetic macular edema (DME), Anti-VEGF agents are safe and effective in DME treatment, there are multiple Anti-VEGF agents, choosing between them is essential to individualize treatment for each patient to achieve the optimum results. PMID:27419238

  5. Over-expression of VEGF165 in the adipose tissue-derived stem cells via the lentiviral vector

    SUN Xiang-zhou; LIU Gui-hua; WANG Zhuo-qing; ZHENG Fu-fu; BIAN Jun; HUANG Yan-ping; GAO Yong; ZHANG Ya-dong; DENG Chun-hua

    2011-01-01

    Background Many researchers studied the possibility of using stem cells as gene therapeutic vector. But few related reports on the adipose tissue-derived stem cells (ADSCs) are available. Therefore we intended to construct a lentiviral VEGF165 expression vector and then infect the ADSCs to produce therapeutic seed cells.Methods EHS1001-68950485313912 clone was mutated by PCR method to produce consensus fragment of VEGF165 transcript (NM_001025368). Lentivirus was enveloped with pGC-FU, pHelper 1.0 and pHelper 2.0 plasmids in 293T cells.And then the ADSCs (multiplicity of infection=20) were transfected with the vectors after titer determination. Stable expression of VEGF165 in ADSCs was confirmed by immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis.Results DNA sequencing and 293T transfection verified VEGF165 was linked to the GFP fused vector. The virus titer is up to 2x10a determined by quantitative PCR. VEGF165 transduced cells could show green fluorescence confirmed by immunofluorescence staining (almost 95%). ELISA analyses could detect out the density of VEGF was 850.86-1202.13pg/ml (mean (923.00±31.22) pg/ml) in the supernatant of VEGF16s-transduced cells but not detected in the GFP-transduced cells (P <0.001) and the Western blotting analyses also confirmed VEGF165 expression in VEGF165-transduced cells.Conclusions The VEGF165 over-expression ADSCs were obtained and may be used as a cell therapeutic tool and may be applied for vascular regeneration, especially in the treatment of erectile dysfunction.

  6. Proteasome inhibitor MG-132 regulates the expression of VEGF in human bronchial epithelial cell line, BEAS-2B

    Xuefan Cui; Kaisheng Yin; Mao Huang; Linfu Zhou

    2005-01-01

    Objective: To explore the effects of MG-132 on the expression of VEGF in bronchial epithelial cell line, BEAS2B. Methods: Semi-quantitive RT-PCR for VEGF mRNA and enzyme-linked immunosorbent assay (ELISA) for VEGF protein were performed. Results: MG-132 increased the expression of VEGF mRNA and protein BEAS-2B cells in time-and concentration-dependent manners. After 24-h stimulation, 25 μmol/L MG-132 increased the maximal levels of VEGF protein in cell-conditioned medium. When the cells were stimulated with cycloheximide(CHX) before treatment with MG-132, the MG-132-induced production of VEGF protein was inhibited compared to the unstimulated cells. Supernatant of condition-medium treatment with MG-132 enhanced the growth of HUVEC.Conclusion: MG-132 induces VEGF gene expression in human bronchial epithelial cells line, BEAS-2B, and the MG-132-induced expression of VEGF may modulate lung tissue injury due to airway inflammation.

  7. Clinical value ofSerumTSH combined with 3 kinds ofVEGF determination in the early diagnosis of papillary thyroid carcinoma

    Ming Zeng

    2015-01-01

    Objective:To discuss the clinical value of Serum TSH combined with 3 kinds of VEGF (VEGF-C, VEGF-D and VEGFR-3) determination in the early diagnosis of papillary thyroid carcinoma (PTC). Method:Selected 37 cases of patients with thyroid benign tumor (Benign group) and 37 cases of patients with PTC (PTC group), then collected the serum of these both groups, to determine the TSH, VEGF-C, VEGF-D and VEGFR-3 levels of all cases by chemiluminescence immunoassay and enzyme linked immunosorbent assay respectively. Through Logistic model, to calculate the curve area of TSH combined with 3 kinds of VEGF.Results:PTC group: VEGF-C, VEGFR-3 and TSH levels were obviously higher than that in Benign group (P<0.05); and VEGF-C, VEGFR-3 and TSH levels inⅢ-Ⅳ period patients were obviously higher than that in I-Ⅱ period patients (P<0.05); AUC area of VEGF-C, VEGFR-3 and TSH were respectively 0.805, 0.736 and 0.710, reached to significance level (P<0.05); AUC area of combined diagnosis was 0.859.Conclusion:VEGF-C, VEGFR-3 and TSH between papillary thyroid carcinoma and thyroid benign tumor had significant difference. Combined determination could improve the early diagnose rate of PTC, and could be regarded as one of the important auxiliary index of PTC early diagnosis.

  8. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets

    Werther, K; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2002-01-01

    contained considerable amounts of VEGF. In isolated lymphocytes and monocytes, VEGF was not present in measurable amounts. The number of neutrophils was significantly (p<0.0001) correlated to VEGF concentrations in lysed whole blood, but not to VEGF concentrations in plasma or serum. The number of platelets...... clotting. CONCLUSION: Circulating neutrophils contain considerable amounts of VEGF that contribute to high VEGF levels in lysed whole blood. VEGF in circulating platelets contributes to high VEGF levels in serum and lysed whole blood. Allowing whole blood samples to clot for between 2 and 6 h before serum......AIM: The sources of increased vascular endothelial growth factor (VEGF) concentrations in peripheral blood from cancer patients are not known in detail. The aim of the present study was to evaluate correlations between the VEGF content in isolated leucocyte subpopulations and VEGF concentrations in...

  9. Ablation of lung tumours

    Gillams, Alice

    2012-01-01

    Abstract Radiofrequency, laser, microwave and cryotherapy have all been used for the ablation of lung tumours. However, radiofrequency ablation (RFA) and microwave ablation are the most widely used technologies. RFA has been successfully applied to tumour measuring from

  10. 68Ga-NODAGA-VEGF121 for in vivo imaging of VEGF receptor expression

    Purpose: Vascular endothelial growth factor (VEGF) is a crucial regulator of angiogenesis. In this study, we labeled VEGF121 with 68Ga using a hydrophilic chelating agent, NODAGA and evaluated the resulting 68Ga-NODAGA-VEGF121 for in vivo imaging of VEGF receptor (VEGFR) expression. Methods: NODAGA-VEGF121 was prepared and its binding affinity for VEGFR2 was measured using 125I-VEGF121. 68Ga-NODAGA-VEGF121 was prepared by labeling NODAGA-VEGF121 with 68GaCl3 followed by purification using a PD-10 column. Human aortic endothelial cell (HAEC) binding studies of 68Ga-NODAGA-VEGF121 were performed at 37 °C for 4 h. MicroPET imaging followed by biodistribution studies were performed in U87MG tumor-bearing mice injected with 68Ga-NODAGA-VEGF121. Immunofluorescence staining of the tumor tissues was performed to verify VEGFR2 expression. Results: Binding affinity of NODAGA-VEGF121 for VEGFR2 was found to be comparable to that of VEGF121. 68Ga-NODAGA-VEGF121 was prepared in 47.8% yield with specific activity of 3.4 GBq/mg. 68Ga-NODAGA-VEGF121 was avidly taken up by HAECs with a time-dependent increase from 9.88 %ID at 1 h to 20.86 %ID at 4 h. MicroPET imaging of mice demonstrated high liver and spleen uptake with clear visualization of tumor at 1 h after injection. ROI analysis of tumors revealed 2.53 ± 0.11 %ID/g at 4 h after injection. In the blocking study, tumor uptake was inhibited by 29% at 4 h. Subsequent biodistribution studies demonstrated tumor uptake of 2.38 ± 0.15 %ID/g. Immunofluorescence staining of the tumor tissues displayed high level of VEGFR2 expression. Conclusions: These results demonstrate that 68Ga-NODAGA-VEGF121 led to VEGFR-specific distribution in U87MG tumor-bearing mice. This study also suggests that altered physicochemical properties of VEGF121 after radiolabeling may affect biodistribution of the radiolabeled VEGF121

  11. Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer

    Chen, Yu-Hsuan [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University, Pharmacological Institute, College of Medicine, Taipei (China); Pan, Shiow-Lin; Wang, Jing-Chi; Teng, Che-Ming [National Taiwan University, Pharmacological Institute, College of Medicine, Taipei (China); Kuo, Sung-Hsin [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University College of Medicine, Department of Internal Medicine, Taipei (China); Cheng, Jason Chia-Hsien [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Taipei (China)

    2014-12-15

    The present study was undertaken to investigate whether radiation induces the expression of vascular endothelial growth factor C (VEGF-C) through activation of the PI3K/Akt/mTOR pathway,subsequently affecting endothelial cells. Radiotherapy-induced tumor micro-lymphatic vessel density (MLVD) was determined in a lung cancer xenograft model established in SCID mice. The protein expression and phosphorylation of members of the PI3K/Akt/mTOR pathway and VEGF-C secretion and mRNA expression in irradiated lung cancer cells were assessed by Western blot analysis, enzyme-linked immunosorbent assays (ELISAs), and reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, specific chemical inhibitors were used to evaluate the role of the PI3K/Akt/mTOR signaling pathway. Conditioned medium (CM) from irradiated control-siRNA or VEGF-C-siRNA-expressing A549 cells was used to evaluate the proliferation of endothelial cells by the MTT assay. Radiation increased VEGF-C expression in a dose-dependent manner over time at the protein but not at the mRNA level. Radiation also up-regulated the phosphorylation of Akt, mTOR, 4EBP, and eIF4E, but not of p70S6K. Radiation-induced VEGF-C expression was down-regulated by LY294002 and rapamycin (both p < 0.05). Furthermore, CM from irradiated A549 cells enhanced human umbilical vein endothelial cell (HUVEC) and lymphatic endothelial cell (LEC) proliferation, which was not observed with CM from irradiated VEGF-C-siRNA-expressing A549 cells. Radiation-induced activation of the PI3K/Akt/mTOR signaling pathway increases VEGF-C expression in lung cancer cells, thereby promoting endothelial cell proliferation. (orig.) [German] Die vorliegende Studie untersucht, ob die Strahlung die Expression von VEGF-C (vascular endothelial growth factor C) mittels Aktivierung des PI3K/Akt/mTOR-Signalwegs induziert und anschliessend die endothelialen Zellen beeinflusst. Die durch Strahlentherapie induzierte Mikrolymphgefaessdichte (MLVD) im Tumor wurde in

  12. Pellet ablation and ablation model development

    A broad survey of pellet ablation is given, based primarily on information presented at this meeting. The implications of various experimental observations for ablation theory are derived from qualitative arguments of the physics involved. The major elements of a more complete ablation theory are then outlined in terms of these observations. This is followed by a few suggestions on improving the connections between theory and experimental results through examination of ablation data. Although this is a rather aggressive undertaking for such a brief (and undoubtedly incomplete) assessment, some of the discussion may help us advance the understanding of pellet ablation. 17 refs

  13. Comparative Phosphoproteomics Analysis of VEGF and Angiopoietin-1 Signaling Reveals ZO-1 as a Critical Regulator of Endothelial Cell Proliferation.

    Chidiac, Rony; Zhang, Ying; Tessier, Sylvain; Faubert, Denis; Delisle, Chantal; Gratton, Jean-Philippe

    2016-05-01

    VEGF and angiopoietin-1 (Ang-1) are essential factors to promote angiogenesis through regulation of a plethora of signaling events in endothelial cells (ECs). Although pathways activated by VEGF and Ang-1 are being established, the unique signaling nodes conferring specific responses to each factor remain poorly defined. Thus, we conducted a large-scale comparative phosphoproteomic analysis of signaling pathways activated by VEGF and Ang-1 in ECs using mass spectrometry. Analysis of VEGF and Ang-1 networks of regulated phosphoproteins revealed that the junctional proteins ZO-1, ZO-2, JUP and p120-catenin are part of a cluster of proteins phosphorylated following VEGF stimulation that are linked to MAPK1 activation. Down-regulation of these junctional proteins led to MAPK1 activation and accordingly, increased proliferation of ECs stimulated specifically by VEGF, but not by Ang-1. We identified ZO-1 as the central regulator of this effect and showed that modulation of cellular ZO-1 levels is necessary for EC proliferation during vascular development of the mouse postnatal retina. In conclusion, we uncovered ZO-1 as part of a signaling node activated by VEGF, but not Ang-1, that specifically modulates EC proliferation during angiogenesis. PMID:26846344

  14. The prolyl hydroxylase inhibitor dimethyloxalylglycine enhances dentin sialophoshoprotein expression through VEGF-induced Runx2 stabilization.

    Saeed Ur Rahman

    Full Text Available Prolyl hydroxylase (PHD inhibitors are suggested as therapeutic agents for tissue regeneration based on their ability to induce pro-angiogenic responses. In this study, we examined the effect of the PHD inhibitor dimethyloxalylglycine (DMOG on odontoblast maturation and sought to determine the underlying mechanism using MDPC-23 odontoblast-like cells. DMOG significantly enhanced matrix mineralization, confirmed by alizarin red staining and by measurement of the calcium content. DMOG dose-dependently increased alkaline phosphatase activity and the expressions of dentin sialophosphoprotein (Dspp and osteocalcin. To determine the underlying events leading to DMOG-induced Dspp expression, we analyzed the effect of DMOG on Runx2. Knockdown of Runx2 using siRNAs decreased Dspp expression and prevented DMOG-induced Dspp expression. DMOG enhanced the transcriptional activity and level of Runx2 protein but not Runx2 transcript, and this enhancement was linked to the inhibitory effects of DMOG on the degradation of Runx2 protein. The vascular endothelial growth factor (VEGF siRNAs profoundly decreased the Runx2 protein levels and inhibited the DMOG-increased Runx2 protein. Recombinant VEGF protein treatment significantly and dose-dependently increased the transcriptional activity and level of the Runx2 protein but not Runx2 transcript. Dspp expression was also enhanced by VEGF. Last, we examined the involvement of the Erk mitogen-activated protein kinase and Pin1 pathway in VEGF-enhanced Runx2 because this pathway can regulate the stability and activity of the Runx2 protein. VEGF stimulated Erk activation, and the inhibitors of Erk and Pin1 hampered VEGF-enhanced Runx2 protein. Taken together, the results of this study provide evidence that DMOG can enhance Dspp expression through VEGF-induced stabilization of Runx2 protein, and thus, suggest that DMOG can be used as a therapeutic tool for enhancing odontoblast maturation in dental procedures.

  15. Emerging Local Ablation Techniques

    Stone, Michael J.; Wood, Bradford J.

    2006-01-01

    Local ablation technologies for hepatic malignancy have developed rapidly in the past decade, with advances in several percutaneous or externally delivered treatment methods including radiofrequency ablation, microwave ablation, laser ablation, and high-intensity focused ultrasound. Research has focused on increasing the size of the ablation zone and minimizing heat-sink effects. More recent developments include improvements in treatment planning and navigation with integration of several ima...

  16. Studies of ablation pressure, ablative acceleration and ablative implosions

    Time and space resolved X-ray spectroscopy have been used to measure ablation rate and ablation pressure on plane targets irradiated by the first and second harmonics of Nd glass laser light. Streaked X-ray shadowgraphy has been applied to the study of ablatively imploded spherical shell targets uniformly irradiated by six 1.05 μm laser beams. The results give a direct measurement of shell acceleration and thus of ablation pressure and show evidence of fluid instability increasing as the shell ratio is varied from 10 to 100. A direct determination of implosion core density is also obtained. (author)

  17. Compartment model predicts VEGF secretion and investigates the effects of VEGF Trap in tumor-bearing mice

    StaceyDFinley

    2013-07-01

    Full Text Available Angiogenesis, the formation of new blood vessels from existing vasculature, is important in tumor growth and metastasis. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF, which has been targeted in numerous anti-angiogenic therapies aimed at inhibiting tumor angiogenesis. Systems biology approaches, including computational modeling, are useful for understanding this complex biological process and can aid in the development of novel and effective therapeutics that target the VEGF family of proteins and receptors. We have developed a computational model of VEGF transport and kinetics in the tumor-bearing mouse, which includes three compartments: normal tissue, blood, and tumor. The model simulates human tumor xenografts and includes human (VEGF121 and VEGF165 and mouse (VEGF120 and VEGF164 isoforms. The model incorporates molecular interactions between these VEGF isoforms and receptors (VEGFR1 and VEGFR2, as well as co-receptors (NRP1 and NRP2. We also include important soluble factors: soluble VEGFR1 (sFlt-1 and α-2-macroglobulin. The model accounts for transport via macromolecular transendothelial permeability, lymphatic flow, and plasma clearance. We have fit the model to available in vivo experimental data on the plasma concentration of free VEGF Trap and VEGF Trap bound to mouse and human VEGF in order to estimate the rates at which parenchymal cells (myocytes and tumor cells and endothelial cells secrete VEGF. Interestingly, the predicted tumor VEGF secretion rates are significantly lower (0.007 – 0.023 molecules/cell/s, depending on the tumor microenvironment than most reported in vitro measurements (0.03 – 2.65 molecules/cell/s. The optimized model is used to investigate the interstitial and plasma VEGF concentrations and the effect of the VEGF-neutralizing agent, VEGF Trap (aflibercept. This work complements experimental studies performed in mice and provides a framework with which to examine the effects of

  18. Comparing protein VEGF inhibitors: In vitro biological studies

    Yu, Lanlan; Liang, Xiao Huan [Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 (United States); Ferrara, Napoleone, E-mail: nf@gene.com [Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 (United States)

    2011-05-06

    Highlights: {yields} VEGF is a mediator of angiogenesis. {yields} VEGF inhibitors have clinical applications in cancer and eye disorders. {yields} Five protein VEGF inhibitors were compared for their ability to inhibit. {yields} VEGF-induced activities in cultured endothelial cells. -- Abstract: VEGF inhibitors are widely used as a therapy for tumors and intravascular neovascular disorders, but limited and conflicting data regarding their relative biological potencies are available. The purpose of the study is to compare different protein VEGF inhibitors for their ability to inhibit VEGF-stimulated activities. We tested ranibizumab, the full-length variant of ranibizumab (Mab Y0317), bevacizumab, the VEGF-TrapR1R2 and Flt(1-3)-IgG in bioassays measuring VEGF-stimulated proliferation of bovine retinal microvascular endothelial cells or chemotaxis of human umbilical vein endothelial cells (HUVEC). The inhibitors were also compared for their ability to inhibit MAP kinase activation in HUVECs following VEGF addition. Ranibizumab, VEGF-TrapR1R2 and Flt(1-3)-IgG had very similar potencies in the bioassays tested. Bevacizumab was over 10-fold less potent than these molecules. Mab Y0317 was over 30-fold more potent than bevacizumab. The findings reported in this manuscript describe important intrinsic characteristics of several VEGF inhibitors that may be useful to design and interpret preclinical or clinical studies.

  19. The relationship of Vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer

    The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). Genomic DNA was isolated from whole blood, and six VEGF (−2578C/A, -2489C/T, -1498 T/C, -634 G/C, +936C/T, and +1612 G/A) gene polymorphisms were analyzed by PCR. Levels of serum VEGF were measured using enzyme-linked immunoassays. Patients with G/G genotype for VEGF -634 G/C gene polymorphism showed a lower response rate (22.2%) than those with G/C or C/C genotype (32.3%, 51.1%; P = 0.034). Patients with the VEGF -634 G/C polymorphism G/C + C/C genotype had a longer progression free survival (PFS) of 4.9 months, compared with the PFS of 3.5 months for those with the G/G (P = 0.043, log-rank test). By multivariate analysis, this G/G genotype of VEGF -634 G/C polymorphism was identified as an independent prognostic factor (Hazard ratio 1.497, P = 0.017). Our data suggest that G/G genotype of VEGF -634 G/C polymorphism is related to the higher serum levels of VEGF, and poor clinical outcome in advanced gastric cancer patients

  20. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology.

    Banks, R E; Forbes, M. A.; Kinsey, S E; Stanley, A; Ingham, E; Walters, C; Selby, P J

    1998-01-01

    Vascular endothelial growth factor (VEGF) is a potent angiogenic factor with a key role in several pathological processes, including tumour vascularization. Our preliminary observations indicated higher VEGF concentrations in serum samples than in matched plasma samples. We have now demonstrated that this difference is due to the presence of VEGF within platelets and its release upon their activation during coagulation. In eight healthy volunteers, serum VEGF concentrations ranged from 76 to ...

  1. Expression of vascular endothelial growth factor (VEGF) in locally invasive prostate cancer is prognostic for radiotherapy outcome

    Purpose: Vascular endothelial growth factor (VEGF) is an important hypoxia-inducible pro-angiogenic protein that has been linked with an adverse survival outcome after radiotherapy in other cancer types: we hypothesized that this may also occur in prostate cancer. A retrospective study was, therefore, carried out to evaluate the potential of tumor VEGF expression to predict radiotherapy outcome in patients with high-risk prostate cancer. Methods and Materials: Fifty patients with locally advanced (T3 N0 M0) tumors of Gleason score ≥6, and who received radiotherapy alone as primary treatment for their disease, were studied. Vascular endothelial growth factor expression was assessed on pretreatment diagnostic tumor biopsies using a semiquantitative immunohistochemical scoring system. The results were analyzed in relation to clinicopathologic factors and patient outcome including biochemical failure and disease-specific mortality. Results: High VEGF expression was associated with a poor prognosis: in univariate log rank analysis, VEGF was the only significant prognostic factor for disease-specific survival (p = 0.035). High VEGF expression also associated with increased Gleason score (p = 0.02), but not posttreatment biochemical failure. Conclusion: High tumor expression of VEGF identified patients at high risk of failure of treatment with radiotherapy. These patients might benefit from additional treatment approaches incorporating anti-angiogenic or hypoxia-specific agents

  2. VEGF system, a multi therapeutic target [Sistema VEGF, um alvo multi-terapêutico

    Daniel L. M. de Aguiar

    2009-08-01

    Full Text Available The ability to modulate the vascular endothelial growth factor system (VEGF is fundamental in thetreatment of several pathophysiologies and in the maintenance of homeostasis. Here, some strategies ofcontrol are discussed, e.g. extracellular actions, monoclonal antibodies and aptamers acting as inhibitors ofVEGF and its receptors (VEGFR. In addition, in the cytoplasm one must include inhibitors of the tyrosine kinasedomain.

  3. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets

    Werther, K; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2002-01-01

    AIM: The sources of increased vascular endothelial growth factor (VEGF) concentrations in peripheral blood from cancer patients are not known in detail. The aim of the present study was to evaluate correlations between the VEGF content in isolated leucocyte subpopulations and VEGF concentrations ...

  4. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2–dependent Ca2+ signaling

    Favia, Annarita; Desideri, Marianna; Gambara, Guido; D’Alessio, Alessio; Ruas, Margarida; Esposito, Bianca; Del Bufalo, Donatella; Parrington, John; Ziparo, Elio; Palombi, Fioretta; Galione, Antony; Filippini, Antonio

    2014-01-01

    Vascular endothelial growth factor (VEGF) and its receptors VEGFR1/VEGFR2 play major roles in controlling angiogenesis, including vascularization of solid tumors. Here we describe a specific Ca2+ signaling pathway linked to the VEGFR2 receptor subtype, controlling the critical angiogenic responses of endothelial cells (ECs) to VEGF. Key steps of this pathway are the involvement of the potent Ca2+ mobilizing messenger, nicotinic acid adenine-dinucleotide phosphate (NAADP), and the specific engagement of the two-pore channel TPC2 subtype on acidic intracellular Ca2+ stores, resulting in Ca2+ release and angiogenic responses. Targeting this intracellular pathway pharmacologically using the NAADP antagonist Ned-19 or genetically using Tpcn2−/− mice was found to inhibit angiogenic responses to VEGF in vitro and in vivo. In human umbilical vein endothelial cells (HUVECs) Ned-19 abolished VEGF-induced Ca2+ release, impairing phosphorylation of ERK1/2, Akt, eNOS, JNK, cell proliferation, cell migration, and capillary-like tube formation. Interestingly, Tpcn2 shRNA treatment abolished VEGF-induced Ca2+ release and capillary-like tube formation. Importantly, in vivo VEGF-induced vessel formation in matrigel plugs in mice was abolished by Ned-19 and, most notably, failed to occur in Tpcn2−/− mice, but was unaffected in Tpcn1−/− animals. These results demonstrate that a VEGFR2/NAADP/TPC2/Ca2+ signaling pathway is critical for VEGF-induced angiogenesis in vitro and in vivo. Given that VEGF can elicit both pro- and antiangiogenic responses depending upon the balance of signal transduction pathways activated, targeting specific VEGFR2 downstream signaling pathways could modify this balance, potentially leading to more finely tailored therapeutic strategies. PMID:25331892

  5. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca2+ signaling.

    Favia, Annarita; Desideri, Marianna; Gambara, Guido; D'Alessio, Alessio; Ruas, Margarida; Esposito, Bianca; Del Bufalo, Donatella; Parrington, John; Ziparo, Elio; Palombi, Fioretta; Galione, Antony; Filippini, Antonio

    2014-11-01

    Vascular endothelial growth factor (VEGF) and its receptors VEGFR1/VEGFR2 play major roles in controlling angiogenesis, including vascularization of solid tumors. Here we describe a specific Ca(2+) signaling pathway linked to the VEGFR2 receptor subtype, controlling the critical angiogenic responses of endothelial cells (ECs) to VEGF. Key steps of this pathway are the involvement of the potent Ca(2+) mobilizing messenger, nicotinic acid adenine-dinucleotide phosphate (NAADP), and the specific engagement of the two-pore channel TPC2 subtype on acidic intracellular Ca(2+) stores, resulting in Ca(2+) release and angiogenic responses. Targeting this intracellular pathway pharmacologically using the NAADP antagonist Ned-19 or genetically using Tpcn2(-/-) mice was found to inhibit angiogenic responses to VEGF in vitro and in vivo. In human umbilical vein endothelial cells (HUVECs) Ned-19 abolished VEGF-induced Ca(2+) release, impairing phosphorylation of ERK1/2, Akt, eNOS, JNK, cell proliferation, cell migration, and capillary-like tube formation. Interestingly, Tpcn2 shRNA treatment abolished VEGF-induced Ca(2+) release and capillary-like tube formation. Importantly, in vivo VEGF-induced vessel formation in matrigel plugs in mice was abolished by Ned-19 and, most notably, failed to occur in Tpcn2(-/-) mice, but was unaffected in Tpcn1(-/-) animals. These results demonstrate that a VEGFR2/NAADP/TPC2/Ca(2+) signaling pathway is critical for VEGF-induced angiogenesis in vitro and in vivo. Given that VEGF can elicit both pro- and antiangiogenic responses depending upon the balance of signal transduction pathways activated, targeting specific VEGFR2 downstream signaling pathways could modify this balance, potentially leading to more finely tailored therapeutic strategies. PMID:25331892

  6. The Relationship between Serum VEGF Expression and PET/CT Images in TNM-staging of Lung Carcinoma

    2007-01-01

    OBJECTIVE To analyze the relationship between the characteristics of PET/CT images for lung carcinoma (LC) TNM staging and the expression of serum VEGF protein.METHODS PET/CT examinations were performed before treatment of 53 patients with LC. The expression of serum VEGF protein was examined using a quantitative sandwich enzyme-linked immunosorbent assay (ELISA R and D system). The relationship was analyzed between PET/CT images for LC T-staging and metastasis (lymph nodes and distance) and serum VEGF expression.RESULTS Based on PET/CT images for LC T-staging, 11 cases were staged as T1, 9 as T2, 18 as T3 and 15 as T4. Mediastinal nodal metastases were found in 22 patients, and distance metastasis in 9. The serum VEGF level in the LC patients was (378.02±180.79) ng/L, showing that there was a significant difference between the patients and healthy subjects (P<0.05).There was no significant difference in the level of serum VEGF between different low T-staged (T1, T2) patients. However, the level of serum VEGF was significantly different between the low T-staged (T1, T2) and high T-staged (T3, T4) patients (P<0.05). The level of the serum VEGF protein in the patients with mediastinal nodal metastasis was (561.50±104.55) ng/L, and indicating that there was a statistical significance (t=12.21, P<0.05) compared to those in the non-metastatic group. The level of serum VEGF in the patients with distance metastasis was (614.11±158.81) ng/L, demonstrating that there was a significant difference (t=5.30, P<0.05) compared to those in the nondistant metastatic group.CONCLUSION ①There is a high level of serum VEGF xpression in LC patients. ②There is a correlation between metastases (lymph nodes and distance) and the level of serum VEGF. ③With an upgrade of the TNM-stage, the level of serum VEGF protein is elevated.

  7. Platelet VEGF and serum TGF-β1 levels predict chemotherapy response in non-small cell lung cancer patients.

    Fu, Bao-Hong; Fu, Zhan-Zhao; Meng, Wei; Gu, Tao; Sun, Xiao-Dong; Zhang, Zhi

    2015-08-01

    We examined the levels of platelet vascular endothelial growth factor (VEGF(PLT)) and serum level of transforming growth factor beta 1 (TGF-β1) in non-small cell lung cancer (NSCLC) patients before and after chemotherapy to assess their clinical value as biomarkers. A total of 115 subjects were recruited at the First Hospital of Qinhuangdao between July 2012 and October 2013, including 65 NSCLC patients receiving chemotherapy (NSCLC group) and 50 healthy controls (control group). All NSCLC patients received gemcitabine plus cisplatin (GP regimen) for a total of two courses. VEGF(PLT) and serum TGF-β1 levels were measured before and after chemotherapy using enzyme-linked immunosorbent assay (ELISA). Platelet count was obtained using the Abbott CD-1600 auto blood analyzer. NSCLC group was categorized into complete response (CR) plus partial response (PR) group and stable disease (SD) plus progressive disease (PD) group based on the results of CT scans obtained 1 week after chemotherapy. Our results revealed that VEGF(PLT) and serum TGF-β1 levels were significantly higher in NSCLC group before chemotherapy, compared to the control group (VEGF(PLT), 0.813 ± 0.072 vs. 0.547 ± 0.024; t = 26.48; P VEGF(PLT) and serum TGF-β1 levels decreased significantly after chemotherapy in CR + PR group in comparison with before chemotherapy (VEGF(PLT), 0.453 ± 0.078 vs. 0.814 ± 0.127; t = 15.51; P VEGF(PLT) and serum TGF-β1 levels were markedly higher after chemotherapy in the SD + PD group in comparison with before chemotherapy (VEGF(PLT), 0.816 ± 0.043 vs. 1.065 ± 0.016; t = 22.38; P VEGF(PLT) and serum TGF-β1 levels, and VEGF(PLT) and TGF-β1 levels correlate with chemotherapy response to GP regimen. Therefore, VEGF(PLT) and serum TGF-β1 levels are valuable biomarkers in clinical monitoring of NSCLC patients. PMID:25820820

  8. The VEGF signaling pathway in cancer: the road ahead

    Steven A. Stacker

    2013-06-01

    Full Text Available The vascular endothelial growth factor (VEGF family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF, play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.

  9. VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

    There is increasing evidence for the presence of cancer stem cells (CSCs) in malignant brain tumors, and these CSCs may play a pivotal role in tumor initiation, growth, and recurrence. Vascular endothelial growth factor (VEGF) promotes the proliferation of vascular endothelial cells (VECs) and the neurogenesis of neural stem cells. Using CSCs derived from human glioblastomas and a retrovirus expressing VEGF, we examined the effects of VEGF on the properties of CSCs in vitro and in vivo. Although VEGF did not affect the property of CSCs in vitro, the injection of mouse brains with VEGF-expressing CSCs led to the massive expansion of vascular-rich GBM, tumor-associated hemorrhage, and high morbidity, suggesting that VEGF promoted tumorigenesis via angiogenesis. These results revealed that VEGF induced the proliferation of VEC in the vascular-rich tumor environment, the so-called stem cell niche

  10. Anthrax lethal toxin suppresses high glucose induced VEGF over secretion through a post-translational mechanism

    Wei-Wei; Zhang; Xin; Wang; Ping; Xie; Song-Tao; Yuan; Qing-Huai; Liu

    2015-01-01

    AIM: To prove anthrax lethal toxin(Le Tx) blocks the mitogen activated protein kinases(MAPKs) activation by degrading the MAPK/ERK kinases(MEKs) to suppress vascular endothelial growth factor(VEGF) secretion.METHODS: Human adult retinal pigmented epithelium(ARPE) cells were cultured and treated with normal glucose, high glucose or high glucose with Le Tx for additional 24, 48 or 72 h for viable cell count. Total RNA from the ARPE was isolated for reverse transcription polymerase chain reaction(RT-PCR). The conditioned medium of ARPE cells treated in different group for 48 h was filtered and diluted to detect the concentration of VEGF by enzyme-linked immunosorbant assays.Evaluate the role of MEK/MAPK pathway in the secretion of VEGF by immunoblotting. RESULTS: In this study, we proved high glucose induced activation of the MAPK extracellular signal-regulated kinase(ERK1/2) and p38 in the ARPE cell line was blocked by anthrax Le Tx. Le Tx also inhibited high glucose induced ARPE cell over proliferation.CONCLUSION: Le Tx suppressed high glucose induced VEGF over secretion in the ARPE cells, mainly through a post-translational mechanism.

  11. Nonequilibrium Ablation of Phenolic Impregnated Carbon Ablator

    Milos, Frank S.; Chen, Yih K.; Gokcen, Tahir

    2012-01-01

    In previous work, an equilibrium ablation and thermal response model for Phenolic Impregnated Carbon Ablator was developed. In general, over a wide range of test conditions, model predictions compared well with arcjet data for surface recession, surface temperature, in-depth temperature at multiple thermocouples, and char depth. In this work, additional arcjet tests were conducted at stagnation conditions down to 40 W/sq cm and 1.6 kPa. The new data suggest that nonequilibrium effects become important for ablation predictions at heat flux or pressure below about 80 W/sq cm or 10 kPa, respectively. Modifications to the ablation model to account for nonequilibrium effects are investigated. Predictions of the equilibrium and nonequilibrium models are compared with the arcjet data.

  12. COX-2, VEGF and tumour angiogenesis.

    Toomey, D P

    2009-06-01

    Epidemiological evidence suggests a protective effective of regular NSAID use against developing cancer. Cyclooxygenase-2, a target of NSAIDs, is upregulated in many cancers and has been associated with increased VEGF production and angiogenesis. Angiogenesis is the formation of new vessels from existing vasculature and as an essential process for tumour development represents an important therapeutic target. Following an extensive review of the literature this article details the current knowledge on the role of COX-2 in tumorigenesis focusing on its relationship to angiogenesis and VEGF production by tumour cells. While COX-2 is clearly detrimental to prognosis and NSAIDs have a beneficial effect, the possibility of COX-2 independent effects being partly or wholly responsible for this benefit cannot be excluded.

  13. Tendon lesion and VEGF-111 injection

    Kaux, Jean-François; Drion, Pierre; Libertiaux, Vincent; Pascon, Frédéric; Colige, Alain; Le Goff, Caroline; Lambert, Charles; Janssen, Lauriane; Nusgens, Betty; Gothot, André; CESCOTTO, Serge; Defraigne, Jean-Olivier; Rickert, Markus; Crielaard, Jean-Michel

    2010-01-01

    Introduction: Tendon lesion is one of the most frequent pathology in sports and by physical workers. This pathology often becomes chronic. For this reason, it is of interest to develop new treatments. Injection of platelet-rich plasma (PRP) seems to be a promising one by releasing growth factors (GF) locally. Among all the GF released by activated platelets, the vascular endothelial growth factor-A (VEGF-A) is known to induce positive effects on vascular function and angiogenesis, and could b...

  14. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma.

    Peng, Hong; Zhang, Qiuyang; Li, Jiali; Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

    2016-03-29

    Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID:26967384

  15. Comparative integromics on VEGF family members.

    Katoh, Yuriko; Katoh, Masaru

    2006-06-01

    VEGF, Hedgehog, FGF, Notch, and WNT signaling pathways network together for vascular remodeling during embryogenesis, tissue regeneration, and carcinogenesis. VEGFA (VEGF), VEGFB, VEGFC, VEGFD (FIGF) and PGF (PlGF) are VEGF family ligands for receptor tyrosine kinases, including VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway. TCF/LEF binding sites within the promoter region of human VEGF family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the 5'-promoter region of human VEGFD gene within AC095351.5 genome sequence, comparative genomics analyses on VEGFD orthologs were further performed. ASB9-ASB11-VEGFD locus at human chromosome Xp22.2 and ASB5-VEGFC locus at human chromosome 4q34 were paralogous regions within the human genome. Human VEGFD mRNA was expressed in lung, small intestine, uterus, breast, neural tissues, and neuroblastoma. Mouse Vegfd mRNA was expressed in kidney, pregnant oviduct, and neural tissues. Chimpanzee VEGFD promoter, cow Vegfd promoter, mouse Vegfd promoter and rat Vegfd promoter were identified within NW_121675.1, AC161065.2, AL732475.6 and AC130036.3 genome sequences, respectively. Three out of four TCF/LEF-binding sites within human VEGFD promoter were conserved in chimpanzee VEGFD promoter, and one in cow Vegfd promoter. TCF/LEF-binding site, not conserved in human VEGFD promoter, occurred in cow, mouse and rat Vegfd promoters. At least five out of six bHLH-binding sites within human VEGFD proximal promoter region were conserved in chimpanzee VEGFD proximal promoter region, while only one in cow Vegfd proximal promoter region. Together these facts indicate that relatively significant promoter evolution occurred among mammalian VEGFD orthologs. Human VEGFD was characterized as a potent target gene of WNT

  16. Expression of VEGF, b-FGF, and their receptors after injection of VEGF on ischemic heart muscle

    XU Xun-yu; SUN Lin; HAN Tao; CHEN Wen-hong; CUI Yong; LI Yan

    2004-01-01

    Objective: To study the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) and their receptors after injection of external VEGF on ischemic heart muscle and to investigate the mechanism of therapeutic myocardial angiogenesis of VEGF. Methods: Standard experimental pigs underwent placement of a left circumflex artery ameroid occluder. Six weeks later, the animals in the experimental group were treated with VEGF (20μg) by direct epicardial injection ( n = 8) and other animals in the control group did not receive any treatment ( n = 8).Four weeks after therapy, the animals were evaluated with regard to mRNA and protein expression of VEGF and b-FGF and their receptors by RT-PCR and Western blotting. Results: The mRNA expression of VEGF and b-FGF and their receptors by RT-PCR expressing as percentage of density ratio to the GAPDH control was increased in experimental group versus control group. The protein expression of VEGF and b-FGF and their receptors by Western blot expressing as percentage of density ratio to the Commassie Blue control was increased in experimental group versus control Group. Conclusion: Exogenous VEGF can induce the expression of endogenous VEGF, b-FGF, and their receptors; b-FGF may play a role in the angiogenesis of VEGF.

  17. Clinicopathologic significance of HIF-1α, p53, and VEGF expression and preoperative serum VEGF level in gastric cancer

    Hypoxia influences tumor growth by inducing angiogenesis and genetic alterations. Hypoxia-inducible factor 1α (HIF-1α), p53, and vascular endothelial growth factor (VEGF) are all important factors in the mechanisms inherent to tumor progression. In this work, we have investigated the clinicopathologic significance of HIF-1α, p53, and VEGF expression and preoperative serum VEGF (sVEGF) level in gastric cancer. We immunohistochemically assessed the HIF-1α, p53, and VEGF expression patterns in 114 specimens of gastric cancer. Additionally, we determined the levels of preoperative serum VEGF (sVEGF). The positive rates of p53 and HIF-1α (diffuse, deep, intravascular pattern) were 38.6% and 15.8%, respectively. The VEGF overexpression rate was 57.9%. p53 and HIF-1α were correlated positively with the depth of invasion (P = 0.015, P = 0.001, respectively). Preoperative sVEGF and p53 levels were correlated significantly with lymph node involvement (P = 0.010, P = 0.040, respectively). VEGF overexpression was more frequently observed in the old age group (≥ 60 years old) and the intestinal type (P = 0.013, P = 0.014, respectively). However, correlations between preoperative sVEGF level and tissue HIF-1α, VEGF, and p53 were not observed. The median follow-up duration after operation was 24.5 months. HIF-1α was observed to be a poor prognostic factor of disease recurrence or progression (P = 0.002). p53, HIF-1α and preoperative sVEGF might be markers of depth of invasion or lymph node involvement. HIF-1α expression was a poor prognostic factor of disease recurrence or progression in patients with gastric cancers

  18. Lung Ablation: Whats New?

    Xiong, Lillian; Dupuy, Damian E

    2016-07-01

    Lung cancer had an estimated incidence of 221,200 in 2015, making up 13% of all cancer diagnoses. Tumor ablation is an important treatment option for nonsurgical lung cancer and pulmonary metastatic patients. Radiofrequency ablation has been used for over a decade with newer modalities, microwave ablation, cryoablation, and irreversible electroporation presenting as additional and possibly improved treatment options for patients. This minimally invasive therapy is best for small primary lesions or favorably located metastatic tumors. These technologies can offer palliation and sometimes cure of thoracic malignancies. This article discusses the current available technologies and techniques available for tumor ablation. PMID:27050331

  19. Ablative Thermal Protection System Fundamentals

    Beck, Robin A. S.

    2013-01-01

    This is the presentation for a short course on the fundamentals of ablative thermal protection systems. It covers the definition of ablation, description of ablative materials, how they work, how to analyze them and how to model them.

  20. Targeting VEGF signalling via the neuropilin co-receptor.

    Djordjevic, S.; Driscoll, P. C.

    2013-01-01

    The blockade of tumour vascularisation and angiogenesis continues to be a focus for drug development in oncology and other pathologies. Historically, targeting vascular endothelial growth factor (VEGF) activity and its association with VEGF receptors (VEGFRs) has represented the most promising line of attack. More recently, the recognition that VEGFR co-receptors, neuropilin-1 and -2 (NRP1 and NRP2), are also engaged by specific VEGF isoforms in tandem with the VEGFRs has expanded the landsca...

  1. Laser ablation principles and applications

    1994-01-01

    Laser Ablation provides a broad picture of the current understanding of laser ablation and its many applications, from the views of key contributors to the field. Discussed are in detail the electronic processes in laser ablation of semiconductors and insulators, the post-ionization of laser-desorbed biomolecules, Fourier-transform mass spectroscopy, the interaction of laser radiation with organic polymers, laser ablation and optical surface damage, laser desorption/ablation with laser detection, and laser ablation of superconducting thin films.

  2. Changes of plasma VEGF levels and liver function in patients with liver cancer before and after interventional treatment

    To explore the effect of the interventional treatment for the angiogenesis and liver function in patients with liver cancer within short time, enzyme linked immunosorbent assay was used to determine the level of VEGF in plasma. The level of liver function was measured through automatic biochemistry analyzer. The results indicated that the level of VEGF in patients with liver cancer decreased after interventional treatment than that of before treatment (P<0.05). The level of total protein, albumin, alkaline phosphatase and total bile acid decreased after interventional treatment (P<0.05). The level of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin and indirect bilirubin were increased than before (P<0.05). The interventional treatment inhibit the expression of the VEGF in the tumor tissue and limited the angiogenesis within short time, but to some extent may caused the injury of the hepatocytes and the synthetic and excremental function in patients with liver cancer. (authors)

  3. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    Sjöström, S; Wibom, C; Andersson, U;

    2010-01-01

    collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs......Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases...

  4. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    Sjöström, S; Wibom, C; Andersson, U;

    2011-01-01

    collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs......Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases...

  5. Hypoxia promotes adipose-derived stem cell proliferation via VEGF

    Phuc Van Pham

    2016-01-01

    Full Text Available Adipose-derived stem cells (ADSCs are a promising mesenchymal stem cell source with therapeutic applications. Recent studies have shown that ADSCs could be expanded in vitro without phenotype changes. This study aimed to evaluate the effect of hypoxia on ADSC proliferation in vitro and to determine the role of vascular endothelial growth factor (VEGF in ADSC proliferation. ADSCs were selectively cultured from the stromal vascular fraction obtained from adipose tissue in DMEM/F12 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic. ADSCs were cultured under two conditions: hypoxia (5% O2 and normal oxygen (21% O2. The effects of the oxygen concentration on cell proliferation were examined by cell cycle and doubling time. The expression of VEGF was evaluated by the ELISA assay. The role of VEGF in ADSC proliferation was studied by neutralizing VEGF with anti-VEGF monoclonal antibodies. We found that the ADSC proliferation rate was significantly higher under hypoxia compared with normoxia. In hypoxia, ADSCs also triggered VEGF expression. However, neutralizing VEGF with anti-VEGF monoclonal antibodies significantly reduced the proliferation rate. These results suggest that hypoxia stimulated ADSC proliferation in association with VEGF production. [Biomed Res Ther 2016; 3(1.000: 476-482

  6. Correlation of the Appearances of DSA with VEGF Expression and Its Clinical Significance in Patients with Primary Hepatocellular Carcinoma

    CHEN Fangman; JIAO Xudong; DU Fang

    2006-01-01

    Objective: To investigate the relationship between the appearances of digital subtraction angiography (DSA) and the serum level of vascular endothelial growth factor (VEGF) in patients with primary hepatocellular carcinoma (HCC). Methods: 24 HCC patients, 30 times DSA were examined, serum VEGF level was measured with the quantitative enzyme linked immunosorbent assay (ELISA) in patients and healthy control subjects in this study. Results: Among DSA for 24 patients with HCC, 18 of 24 cases showed hepatic artery blood supply of tumor. Four of 24 cases showed portal vein blood supply of tumor,1 of 24 cases showed superior mesenteric artery blood supply of tumor and artery-venous shunt formation, and there was no blood supply to tumor in one case. Serum VEGF level in HCC[(χ+s)194.5±14.2] ng/L was significant elevated to those in patients comparing with those of the normal controls (132.4±47.9)ng/L and marked differences (P<0.01). Conclusion: During the cases for plenty blood supply or arteryvenous shunt formation in patients with HCC, serum VEGF level markedly elevated in the patients of HCC. VEGF expression was significantly related to intrahepatic dissemination, recurrence and metastasis in patients with HCC.

  7. VEGF is deposited in the subepithelial matrix at the leading edge of branching airways and stimulates neovascularization in the murine embryonic lung.

    Healy, A M; Morgenthau, L; Zhu, X; Farber, H W; Cardoso, W V

    2000-11-01

    We used whole lung cultures as a model to study blood vessel formation in vitro and to examine the role that epithelial-mesenchymal interactions play during embryonic pulmonary vascular development. Mouse lungs were isolated at embryonic day 11.5 (E11.5) and cultured for up to 4 days prior to blood vessel analysis. Platelet endothelial cell adhesion molecule-1 (PECAM/CD31) and thrombomodulin (TM/CD141) immunolocalization demonstrate that vascular development occurs in lung cultures. The vascular structures identified in lung cultures first appear as a loosely associated plexus of capillary-like structures that with time surround the airways. To investigate the potential role of vascular endothelial cell growth factor (VEGF) during pulmonary neovascularization, we immunolocalized VEGF in embryonic lungs. Our data demonstrate that VEGF is uniformly present in the airway epithelium and the subepithelial matrix of E11.5 lungs. At later time points, E13.5 and E15.5, VEGF is no longer detected in the proximal airways, but is restricted to the branching tips of airways in the distal lung. RT-PCR analysis reveals that VEGF(164) is the predominant isoform expressed in lung cultures. Grafting heparin-bound VEGF(164) beads onto lung explants locally stimulates a marked neovascular response within 48 hr in culture. Semi-quantitative RT-PCR reveals an 18% increase in PECAM mRNA in VEGF(164)-treated whole lung cultures as compared with untreated cultures. The restricted temporal and spatial expression of VEGF suggests that matrix-associated VEGF links airway branching with blood vessel formation by stimulating neovascularization at the leading edge of branching airways. PMID:11066091

  8. VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model

    Wu, Florence T.H.; Stefanini, Marianne O.; Gabhann, Feilim Mac; Kontos, Christopher D.; Annex, Brian H; Popel, Aleksander S.

    2010-01-01

    Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, the growth of new capillaries from existing microvasculature. In peripheral arterial disease (PAD), lower extremity muscle ischemia develops downstream of atherosclerotic obstruction. A working hypothesis proposed that the maladaptive overexpression of soluble VEGF receptor 1 (sVEGFR1) in ischemic muscle tissues, and its subsequent antagonism of VEGF bioactivity, may contribute to the deficient angiogenic response i...

  9. Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable anti-angiogenesis effect in vivo.

    Qin Wang

    Full Text Available VEGF family factors are known to be the principal stimulators of abnormal angiogenesis, which play a fundamental role in tumor and various ocular diseases. Inhibition of VEGF is widely applied in antiangiogenic therapy. Conbercept is a novel decoy receptor protein constructed by fusing VEGF receptor 1 and VEGF receptor 2 extracellular domains with the Fc region of human immunoglobulin. In this study, we systematically evaluated the binding affinity of conbercept with VEGF isoforms and PlGF by using anti-VEGF antibody (Avastin as reference. BIACORE and ELISA assay results indicated that conbercept could bind different VEGF-A isoforms with higher affinity than reference. Furthermore, conbercept could also bind VEGF-B and PlGF, whereas Avastin showed no binding. Oxygen-induced retinopathy model showed that conbercept could inhibit the formation of neovasularizations. In tumor-bearing nude mice, conbercept could also suppress tumor growth very effectively in vivo. Overall, our study have demonstrated that conbercept could bind with high affinity to multiple VEGF isoforms and consequently provide remarkable anti-angiogenic effect, suggesting the possibility to treat angiogenesis-related diseases such as cancer and wet AMD etc.

  10. RNA Activation of the Vascular Endothelial Growth Factor Gene (VEGF) Promoter by Double-Stranded RNA and Hypoxia: Role of Noncoding VEGF Promoter Transcripts.

    Lopez, Pascal; Wagner, Kay-Dietrich; Hofman, Paul; Van Obberghen, Emmanuel

    2016-05-15

    RNA activation (RNAa) is a gene regulation process in which promoter-targeted short double-stranded RNAs (dsRNAs) or microRNAs (miRs) induce target gene expression at the transcriptional level. Here, we investigate the presence of cryptic promoter transcripts within the VEGF promoter. Single-strand sense and antisense noncoding vascular endothelial growth factor (NcVEGF) promoter transcripts are identified, and their respective expression is studied in cells transfected with a VEGF promoter targeted dsRNA, namely, dsVEGF706, in hypoxic cells and in human malignant lung tissues. Interestingly, in dsVEGF706-transfected, as well as in hypoxic cells, NcVEGF expression levels increase coordinately with coding VEGF expression. Ago2 interaction with both sense and antisense NcVEGFs is increased in hypoxic cells, whereas in dsVEGF706-transfected cells, Ago2 and the antisense strand of the dsRNA interact specifically with the sense NcVEGF transcript. Furthermore, both dsVEGF706 and ectopic NcVEGF transcripts are able to activate the VEGF promoter endogenously present or in a reporter construct. Finally, using small interfering RNA targeting Ago2, we show that RNAa plays a role in the maintenance of increased VEGF and NcVEGF expression after hypoxia. Given the central role of VEGF in major human diseases, including cancer, this novel molecular mechanism is poised to reveal promising possibilities for therapeutic interventions. PMID:26976645

  11. Intravoxel Incoherent Motion Diffusion Weighted MR Imaging for Monitoring the Instantly Therapeutic Efficacy of Radiofrequency Ablation in Rabbit VX2 Tumors without Evident Links between Conventional Perfusion Weighted Images.

    Ziyi Guo

    Full Text Available To investigate the intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI as a potential valuable marker to monitor the therapy responses of VX2 to radiofrequency ablation (RF Ablation.The institutional animal care and use committee approved this study. In 10 VX2 tumor-bearing rabbits, IVIM-DWI examinations were performed with a 3.0T imaging unit by using 16 b values from 0 to 800 sec/mm2. The true diffusion coefficient (D, pseudodiffusion coefficient (D* and perfusion fraction (f of tumors were compared between before and instantly after RF Ablation treatment. The differences of D, D* and f and conventional perfusion parameters (from perfusion CT and dynamic enhanced magnetic resonance imaging, DCE-MRI in the coagulation necrosis area, residual unablated area, untreated area, and normal control had been calculated by compared t-test. The correlation between f or D* with perfusion weighted CT including blood flow, BF (milliliter per 100 mL/min, blood volume, BV (milliliter per 100 mL/min, and capillary permeability-surface area, PMB (as a fraction or from DCE-MRI: transfer constant (Ktrans, extra-vascular extra-cellular volume fraction (Ve and reflux constant (Kep values had been analyzed by region-of-interest (ROI methods to calculate Pearson's correlation coefficients.In the ablated necrosis areas, f and D* significantly decreased and D significantly increased, compared with residual unblazed areas or untreated control groups and normal control groups (P < 0.001. The IVIM-DWI derived f parameters showed significant increases in the residual unablated tumor area. There was no significant correlations between f or D* and conventional perfusion parameters.The IVIM-DW derived f, D and D* parameters have the potential to indicate therapy response immediately after RF Ablation treatment, while no significant correlations with classical tumor perfusion metrics were derived from DCE-MRI and perfusion-CT measurements.

  12. Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism

    Ahluwalia, Amrita [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Jones, Michael K. [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Medicine, University of California, Irvine, CA (United States); Szabo, Sandor [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Pathology, University of California, Irvine, CA (United States); Tarnawski, Andrzej S., E-mail: amrita.ahluwalia@va.gov [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Medicine, University of California, Irvine, CA (United States)

    2013-08-09

    Highlights: •Malignant colonic epithelial cells express VEGF and its receptors. •Cultured colon cancer cells secrete VEGF into the medium. •Inhibition of VEGF receptor significantly decreases colon cancer cell proliferation. •VEGF is critical for colon cancer cell growth. -- Abstract: Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. Material and methods: We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n = 43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. Results: Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. Conclusions: Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is

  13. Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism

    Highlights: •Malignant colonic epithelial cells express VEGF and its receptors. •Cultured colon cancer cells secrete VEGF into the medium. •Inhibition of VEGF receptor significantly decreases colon cancer cell proliferation. •VEGF is critical for colon cancer cell growth. -- Abstract: Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. Material and methods: We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n = 43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. Results: Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. Conclusions: Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is

  14. Exercise-Induced VEGF Transcriptional Activation in Brain, Lung and Skeletal Muscle

    Tang, Kechun; Xia, Feng Cheng; Wagner, Peter D.; Breen, Ellen C.

    2009-01-01

    Muscle VEGF expression is upregulated by exercise. Whether this VEGF response is regulated by transcription and/or post-transcriptional mechanisms is unknown. Hypoxia may be responsible: myocyte PO2 falls greatly during exercise and VEGF is a hypoxia-responsive gene. Whether exercise induces VEGF expression in other organs important to acute physical activity is also unknown. To address these questions, we created a VEGF/Luciferase reporter mouse and measured VEGF transcription, mRNA and prot...

  15. VEGF165b in the developing vasculatures of the fetal human eye

    Baba, Takayuki; McLeod, D. Scott; Edwards, Malia M.; Merges, Carol; Sen, Tanusree; Sinha, Debasish; Lutty, Gerard A.

    2016-01-01

    VEGF165b is an anti-angiogenic form of VEGF165 produced by alternative splicing. The localization of pro-angiogenic VEGF165 and anti-angiogenic VEGF165b was investigated during development of the vasculatures in fetal human eyes from 7 to 21 weeks gestation (WG). The fetal vasculature of vitreous, which includes tunica vasculosa lentis (TVL), had moderate VEGF165 immunoreactivity at 7WG and very little VEGF165b. Both forms were elevated at 12WG. VEGF165 then decreased around 17WG when the TVL regresses but VEGF165b remained elevated. In choroid, VEGF165 was present in forming choriocapillaris (CC) and retinal pigment epithelium (RPE) at 7WG while VEGF165b was present in CC and mesenchymal precursors within the choroidal stroma. By 21WG, both forms were elevated in RPE and choroidal blood vessels but VEGF165b was apical and VEGF165 basal in RPE. Diffuse VEGF165 immunoreactivity was prominent in 12WG innermost retina where blood vessels will form while VEGF165b was present in most CXCR4+ progenitors in the inner neuroblastic layer and migrating angioblasts in the putative nerve fiber layer. By 21WG, VEGF165 was present in nerve fibers and VEGF165b in inner Muller cell process. The localization of VEGF165b was distinctly different from VEGF165 both spatially and temporally and it was often associated with nucleus in progenitors. PMID:22275161

  16. Changing paradigms of anti-VEGF in the Indian scenario

    P Mahesh Shanmugam

    2014-01-01

    Full Text Available Anti-vascular endothelial growth factors (VEGF agents have revolutionized the treatment of retinal diseases. Use of anti-VEGF agents in the Indian Scenario present some unique challenges considering the absence of compounding pharmacies, poor penetrance of health insurance and limited affordability of the citizens of a developing economy. To study the changing paradigms of anti-VEGF use in the Indian scenario, all articles published by Indian authors, data from web-based surveys amongst Indian vitreo-retinal specialists were reviewed. In the paucity of compounding pharmacies in India, fractionation and injection techniques differ from those of developed countries. Frequent anti-VEGF monotherapy offers the best anatomical and visual results, but economics of scale do not allow the same in the Indian scenario, resulting in PRN dosing and combination of anti-VEGF with laser photocoagulation, being the commonly employed treatment protocols.

  17. Radiofrequency ablation in dermatology

    Sachdeva Silonie

    2007-01-01

    Full Text Available Radiofreqeuency ablation is a versatile dermatosurgical procedure used for surgical management of skin lesions by using various forms of alternating current at an ultra high frequency. The major modalities in radiofrequency are electrosection, electrocoagulation, electrodessication and fulguration. The use of radiofrequency ablation in dermatosurgical practice has gained importance in recent years as it can be used to treat most of the skin lesions with ease in less time with clean surgical field due to adequate hemostasis and with minimal side effects and complications. This article focuses on the major tissue effects and factors influencing radiofrequency ablation and its application for various dermatological conditions.

  18. Liver tumor ablation

    Minimal-invasive techniques for ablation of primary and secondary hepatic tumors gain increasingly clinical importance. This is especially true since surgical resection and classic chemotherapy is successful only in a limited number of patients. Local ablative methods incorporate chemo- (percutaneous alcohol instillation, transarterial chemoembolization), thermo- (radiofrequency-, laser-, microwave-, cryoablation, high intensive focused ultrasound) and radio-ablative techniques (interstitial brachytherapy, selective internal radiotherapy). Regarding their implementation and specific effects these methods are varying widely, nevertheless all of them have a high therapeutical efficacy together with a low complication rate in common - correct application presumed. The knowledge on specific indications and contraindications is crucial to implement these methods into multimodality therapy concepts. (orig.)

  19. VEGF and Pleiotrophin Modulate the Immune Profile of Breast Cancer

    Lynn, Kristi D.; Roland, Christina L. [Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8593 (United States); Brekken, Rolf A., E-mail: rolf.brekken@utsouthwestern.edu [Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8593 (United States); Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8593 (United States)

    2010-05-26

    Angiogenesis, the sprouting of the existing vascular network to form new vessels, is required for the growth of solid tumors. For this reason, the primary stimulant of angiogenesis, vascular endothelial growth factor-A (VEGF), is an attractive target for tumor therapy. In fact, there are currently numerous anti-VEGF therapies in clinical development for the treatment of various cancers, including breast cancer. VEGF signals through two primary VEGF receptors, VEGFR1 and VEGFR2. VEGFR2 is the primary angiogenic receptor, and VEGFR1 has been implicated in macrophage chemotaxis and tumor cell survival and invasion. It has only been appreciated recently that the VEGFRs are expressed not only on endothelial cells and tumor cells but also on many host immune cells. Therefore, to better understand the effects of anti-VEGF therapy it is important to consider the effects of VEGF on all cells in the tumor microenvironment, including immune cells. Bevacizumab (Avastin{sup ®}, Genetech), which binds VEGF and inhibits interaction with VEGFR1 and VEGFR2, was approved for the treatment of metastatic HER2/NEU-negative breast cancer in 2008, however, the majority of human mammary tumors are either innately resistant or will acquire resistance to anti-VEGF therapy. This suggests that these tumors activate alternate angiogenesis pathways. Pleiotrophin (PTN) is an important angiogenic cytokine in breast cancer and is expressed at high levels in approximately 60% of human breast tumors. PTN functions as an angiogenic factor and promotes remodeling of the tumor microenvironment as well as epithelial-mesenchymal transition (EMT). In addition, PTN can have profound effects on macrophage phenotype. The present review focuses on the functions of VEGF and PTN on immune cell infiltration and function in breast cancer. Furthermore, we will discuss how anti-VEGF therapy modulates the immune cell profile.

  20. Microwave Ablation of Hepatic Malignancy

    Lubner, Meghan G.; Brace, Christopher L.; Ziemlewicz, Tim J.; Hinshaw, J. Louis; Lee, Fred. T.

    2013-01-01

    Microwave ablation is an extremely promising heat-based thermal ablation modality that has particular applicability in treating hepatic malignancies. Microwaves can generate very high temperatures in very short time periods, potentially leading to improved treatment efficiency and larger ablation zones. As the available technology continues to improve, microwave ablation is emerging as a valuable alternative to radiofrequency ablation in the treatment of hepatic malignancies. This article rev...

  1. Clinical effect observation of VEGF expression interfered by Thalidomide combined with radiotherapy in esophageal cancer treatment

    Objective: To prospectively study the dynamic variation of vascular endothelial growth factor (VEGF), the short-term efficiency and the tolerability of the esophageal cancer patients treated by radiotherapy combined with thalidomide. Methods: The serum samples of 86 esophageal cancer patients were collected before, during and after the radiotherapy. The VEGF levels were assayed by enzyme-linked immunosorbent assay (ELISA). 3 patients interrupted the treatment because of intolerance radiotherapy. Based on the changes of VEGF level, 32 esophageal cancer cases whose VEGF levels increased or remained were assigned to the group to which thalidomide was given during the whole course of radiotherapy. The rest 51 patients whose VEGF level decreased received radiotherapy without thalidomide during the whole course.In addition,30 healthy cases were included in control group. Then the efficiency and safety of the introduction of thalidomide in radiotherapy were investigated. Results: The VEGF levels of 86 esophageal cancer cases were significantly higher than the 30 healthy control cases (t=5.07, P<0.01), which were also correlated with the primary tumor size (t=4.55, P<0.01), lymph node metastasis (t=7.50, P<0.01), histological type (F=3.40, P<0.01) and clinical stage (t=2.52, P<0.01). However, it was irrelevant to the lesion site,distant metastasis, X-ray pathologic type, gender or age (P>0.05). For the thalidomide involved group, the VEGF level after radiotherapy was significantly lower than during radiotherapy (t=2.37, P<0.05) with an effective rate of 71.88%. For the rest 51 cases without using thalidomide, the effective rate was 78.43% yet there was no significant difference between the VEGF levels during and after radiotherapy (t=0.18, P>0.05). 62.50% patients reported symptoms of dizzy and burnout after using thalidomide, while this incidence was 15.69% for the rest patients (χ2=19.28, P=0.000). For the groups with or without thalidomide combination, the sleepiness

  2. femtosecond laser ablation

    Margetic, Vanja

    2003-01-01

    Femtosecond laser ablation was investigated as a solid sampling method for elemental chemical analysis. In comparison to the sampling with longer laser pulses, two aspects could be improved by using ultrashort pulses: elimination of the elemental fractionation from the ablation crater, which is necessary for an accurate quantitative analysis, and better control of the material removal (especially for metals), which increases the spatial resolution of microanalysis. Basic aspects of ultrashort...

  3. Engineered Conformation-dependent VEGF Peptide Mimics Are Effective in Inhibiting VEGF Signaling Pathways

    Vicari, Daniele; Foy, Kevin C.; Liotta, Eric M.; Kaumaya, Pravin T.P.

    2011-01-01

    Angiogenesis, or formation of new blood vessels, is crucial to cancer tumor growth. Tumor growth, progression, and metastasis are critically influenced by the production of the pro-angiogenic vascular endothelial growth factor (VEGF). Promising anti-angiogenic drugs are currently available; however, their susceptibilities to drug resistance and long term toxicity are serious impediments to their use, thus requiring the development of new therapeutic approaches for safe and effective angiogeni...

  4. Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

    Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Our findings suggest that chronic inhibition of tumor cell-derived VEGF

  5. Measurement of circulating levels of VEGF-A,-C,and -D and their receptors,VEGFR-1 and -2 in gastric adenocarcinoma

    Mansour S Al-Houndhd; A Al-Shukaili; M Al-Nabhani; B Al-Bahrani; IA Burney; A Rizivi; SS Ganguly

    2008-01-01

    AIM: To analyze the serum levels and prognostic significance of vascular endothelial growth factor (VEGF) -A,-C,and -D,and their receptors,VEGFR-1 and -2 in gastric adenocarcinomas.METHODS: The serum levels of VEGF family members were measured in 76 control subjects and 76 patients with gastric adenocarcinoma using an enzyme-linked immunosorbent assay (ELISA).These measurements were correlated with clinco-pathological features and survival rates.RESULTS: The serum levels of VEGF-A and its receptor,VEGFR-1,were significantly higher in patients with gastric cancer than in healthy donors (t = 2.3,P = 0.02 and t = 4.2,P<0.0001,respectively).In contrast,the serum levels of VEGF-D were significantly higher in control subjects than in patients (t = 2.9,P = 0.004).There was no significant difference in serum levels of VEGF-C and VEGFR-2 between patients and controls.VEGF-C was associated with advanced tumor stage and presence of metastasis.VEGFR-1 was associated with metastasis,advanced overall stage,tumor differentiation and survival.VEGFR-2 levels were associated with poor tumor differentiation.There was no significant prognostic value for any of the VEGF family members or their receptors except for VEGFR-1 where high levels were associated with a poor overall survival.CONCLUSION: Serum VEGF levels vary significantly in the same cohort of patients with variable clinicopathological features and prognostic values.The simultaneous measurement of VFGF receptors levels in sera may overcome the limitations of a single biomarker assay.

  6. The nexus between VEGF and NFκB orchestrates a hypoxia-independent neovasculogenesis.

    Michael DeNiro

    Full Text Available Nuclear Factor-Kappa B [NFκB] activation triggers the elevation of various pro-angiogenic factors that contribute to the development and progression of diabetic vasculopathies. It has been demonstrated that vascular endothelial growth factor [VEGF] activates NFκB signaling pathway. Under the ischemic microenvironments, hypoxia-inducible factor-1 [HIF-1] upregulates the expression of several proangiogenic mediators, which play crucial roles in ocular pathologies. Whereas YC-1, a soluble guanylyl cyclase [sGC] agonist, inhibits HIF-1 and NFκB signaling pathways in various cell and animal models. Throughout this investigation, we examined the molecular link between VEGF and NFκB under a hypoxia-independent microenvironment in human retinal microvascular endothelial cells [hRMVECs]. Our data indicate that VEGF promoted retinal neovasculogenesis via NFκB activation, enhancement of its DNA-binding activity, and upregulating NFκB/p65, SDF-1, CXCR4, FAK, αVβ3, α5β1, EPO, ET-1, and MMP-9 expression. Conversely, YC-1 impaired the activation of NFκB and its downstream signaling pathways, via attenuating IκB kinase phosphorylation, degradation and activation, and thus suppressing p65 phosphorylation, nuclear translocation, and inhibiting NFκB-DNA binding activity. We report for the first time that the nexus between VEGF and NFκB is implicated in coordinating a scheme that upregulates several pro-angiogenic molecules, which promotes retinal neovasculogenesis. Our data may suggest the potential use of YC-1 to attenuate the deleterious effects that are associated with hypoxia/ischemia-independent retinal vasculopathies.

  7. The kinetics of VEGF and MCP-1 in the second vitrectomy cases with proliferative diabetic retinopathy.

    Sassa, Y; Yoshida, S; Ishikawa, K; Asato, R; Ishibashi, T; Kono, T

    2016-05-01

    PurposeTo determine whether the concentrations of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein (MCP)-1 in the vitreous changed after vitrectomy in patients with proliferative diabetic retinopathy (PDR).ParticipantsTwenty-one eyes of 21 patients who needed a second surgery for PDR were included. The reasons for the second surgery were tractional retinal detachment (TRD), neovascular glaucoma, persistent vitreous hemorrhage, macular pucker, and secondary intraocular lens (IOL) implant.MethodsWe measured the VEGF and MCP-1 levels using sandwich enzyme-linked immunosorbent assays in vitreous samples collected from patients with PDR before pars plana vitrectomy (without IOL implantation), and from the same patients during the second surgery.ResultsThere was not significant change in mean VEGF concentrations when comparing first (0.81±0.88 ng/ml) and second surgeries (1.09±1.51 ng/ml). The MCP-1 level was significantly elevated at the time of second surgery (2.20±2.21 ng/ml) compared with the first vitrectomy (0.72±0.57 ng/ml). The MCP-1 levels of the second surgery cases with TRD (3.18±2.27 ng/ml) increased significantly compared with those with other complications (1.72±2.10 ng/ml).ConclusionsAt the second vitrectomy, VEGF did not change significantly in the vitreous of the patients examined. The MCP-1 concentration was markedly elevated at the second vitrectomy, implying an association between the prolonged inflammation after vitrectomy and complications, especially TRD. PMID:26915745

  8. Analysis of diabetic retinopathy biomarker VEGF gene by computational approaches

    Jayashree Sadasivam

    2012-08-01

    Full Text Available Diabetic retinopathy, the most common diabetic eye disease, is caused by changes in the blood vessels of the retina which remains the major cause. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. One of the biomarker for Diabetic retinopathy has been identified as Vascular Endothelial Growth Factor ( VEGF gene by computational analysis. VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signalling proteins involved in both vasculogenesis and angiogenesis, Over expression of VEGF can cause vascular disease in the retina of the eye and other parts of the body. Drugs can inhibit VEGF and control or slowdown those disease. Computational analysis of VEGF with other  genes responsible for diabetic retinopathy were done  by aligning those genes by pair wise and multiple sequence alignments. MSA shows VEGF’s role in diabetic retinopathy and its  related with other genes and proteins responsible for pathogenesis of diabetic retinopathy. Also  the determination of the promoter and conserved domain of  VEGF gene  help us to identify  its expression levels. Thus molecular docking studies were carried out  to analyse the biomarker VEGF, that helps in treatment of diabetic retinopathy which is proliferative in nature due to uncontrolled angiogenesis. Normal 0 false false false EN-US X-NONE X-NONE

  9. VEGF-specific siRNAs modified with 2′-deoxy effectively suppress VEGF expression and inhibit growth of nasopharyngeal carcinoma xenograft in a mouse model

    2008-01-01

    Vascular endothelial growth factor (VEGF) is up-regulated in the vast majority of human tumors. The up-regulation of VEGF not only plays important roles in tumor angiogenesis, but also provides a target for tumor treatment with small interfering RNA (siRNA) that targets VEGF; however, it is unclear whether a quite high up-regulation of VEGF will affect the efficiency of RNA interference strategies targeting VEGF. A high level expression of VEGF was found in CNE cells from a nasopharyngeal carcinoma cell line. In this study, we investigate whether VEGF-specific siRNAs can effectively suppress VEGF expression in CNE cells, and study the methods for the use of VEGF-specific siRNAs as potential therapeutic agents. CNE cells with high VEGF expression induced by hypoxia were transfected with VEGF-specific siRNAs. The expression of VEGF was effectively suppressed by VEGF-specific siRNAs, measured by ELISA, Western blot analysis and RT-PCR. Furthermore, experiments in nude mice bearing nasopharyngeal carcinoma xenograft were initiated 5 d after injection of CNE cells. VEGF-specific siRNAs were modified with 2′-deoxy, then injected into the tumors, and a liposome-mediated siRNA transfection system and ultrasound exposure were used to help delivery of the siRNAs. Tumor growth was reduced significantly after 3 weeks’ treatment. These studies suggest that VEGF-specific siRNAs still can effectively suppress VEGF expression even in tumor cell lines with a relatively high level of VEGF expression, such as CNE, and VEGF-specific siRNAs modified with 2′-deoxy can be used as potential agents for tumor therapy.

  10. VEGF stimulates intramembranous bone formation during craniofacial skeletal development.

    Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R; Berendsen, Agnes D

    2016-01-01

    Deficiency of vascular endothelial growth factor A (VEGF) has been associated with severe craniofacial anomalies in both humans and mice. Cranial neural crest cell (NCC)-derived VEGF regulates proliferation, vascularization and ossification of cartilage and membranous bone. However, the function of VEGF derived from specific subpopulations of NCCs in controlling unique aspects of craniofacial morphogenesis is not clear. In this study a conditional knockdown strategy was used to genetically delete Vegfa expression in Osterix (Osx) and collagen II (Col2)-expressing NCC descendants. No major defects in calvaria and mandibular morphogenesis were observed upon knockdown of VEGF in the Col2(+) cell population. In contrast, loss of VEGF in Osx(+) osteoblast progenitor cells led to reduced ossification of calvarial and mandibular bones without affecting the formation of cartilage templates in newborn mice. The early stages of ossification in the developing jaw revealed decreased initial mineralization levels and a reduced thickness of the collagen I (Col1)-positive bone template upon loss of VEGF in Osx(+) precursors. Increased numbers of proliferating cells were detected within the jaw mesenchyme of mutant embryos. Explant culture assays revealed that mandibular osteogenesis occurred independently of paracrine VEGF action and vascular development. Reduced VEGF expression in mandibles coincided with increased phospho-Smad1/5 (P-Smad1/5) levels and bone morphogenetic protein 2 (Bmp2) expression in the jaw mesenchyme. We conclude that VEGF derived from Osx(+) osteoblast progenitor cells is required for optimal ossification of developing mandibular bones and modulates mechanisms controlling BMP-dependent specification and expansion of the jaw mesenchyme. PMID:26899202

  11. Anti-VEGF antibody treatment accelerates polycystic kidney disease.

    Raina, Shagun; Honer, Michael; Krämer, Stefanie D; Liu, Yang; Wang, Xueqi; Segerer, Stephan; Wüthrich, Rudolf P; Serra, Andreas L

    2011-10-01

    Polycystic kidney growth implies expansion of the vasculature, suggesting that vascular endothelial growth factor (VEGF)-dependent processes play a critical role and that VEGF is a putative therapeutic target. Whether an anti-VEGF antibody improves renal cystic disease has not been determined. We administrated 5 mg/kg B20.4.1, an anti-VEGF-A antibody, or vehicle intraperitoneally twice weekly to 4-wk-old male normal (+/+) and cystic (Cy/+) Han:SPRD rats for 6 wk. Renal function, urinary protein excretion, organ/body weight ratios, cyst volume, tubular epithelial cell (TEC) proliferation, renal VEGF, hypoxia-inducible factor (HIF)-1α and -2α expression, renal histology, and kidney hypoxia visualized by [(18)F]fluoromisonidazole positron emission tomography were assessed. The treated compared with untreated +/+ rats had lower TEC proliferation rates, whereas Cy/+ rats receiving B20.4.1 displayed an increased proximal TEC proliferation rate, causing enhanced cyst and kidney growth. The +/+ and Cy/+ rats receiving B20.4.1 had severe renal failure and extensive glomerular damage. Proteinuria, which was highest in anti-VEGF-treated Cy/+ and lowest in untreated normal littermates, was positively correlated with renal HIF-1α and negatively correlated with VEGF expression. The untreated Cy/+ vs. +/+ rats had higher overall [(18)F]fluoromisonidazole uptake. The +/+ rats receiving B20.4.1 vs. untreated had increased [(18)F]fluoromisonidazole uptake, whereas the uptake was unchanged among treated vs. untreated Cy/+ animals. In conclusion, B20.4.1 caused an exaggerated cystic response of the proximal tubules in cystic rats and severe kidney injury that was associated with low renal VEGF and high HIF-1α levels. Anti-VEGF drug therapy may therefore not be a treatment option for polycystic kidney disease. PMID:21677148

  12. Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells

    Timoshenko, A V; Rastogi, S; P. K. Lala

    2007-01-01

    Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin α9β1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231,...

  13. Gene Expression of VEGF-A and VEGF-C in Peripheral Blood Mononuclear Cells of Iranian Patients with Acute Myeloid Leukemia

    Mohammad Reza Aliparasti

    2013-06-01

    Full Text Available OBJECTIVE: The crucial role of angiogenesis in the pathophysiology of acute myeloid leukemia (AML has been proposed. One of the key regulators of angiogenesis is the vascular endothelial growth factor (VEGF. Among the VEGF family, it has been observed that VEGF-A and VEGF-C are expressed by AML cells and mediate leukemic cell proliferation, survival, and resistance to chemotherapy. Emerging evidence, however, suggests that elevated levels of VEGF or a proangiogenic phenotype may impede, rather than promote, early tumor development and progression. As the significance of VEGF-A and VEGF-C levels in the pathogenesis of AML has not been clarified well, the aim of this study is to evaluate gene expression of these angiogenesis promoters and its possible prognostic value in peripheral blood mononuclear cells of Iranian patients with AML. METHODS: We investigated the mRNA expression of VEGF-A and VEGF-C in peripheral blood mononuclear cells of 27 patients with newly diagnosed AML and 28 healthy controls by quantitative real-time PCR. RESULTS: Expression of VEGF-C mRNA was significantly lower in AML patients than in healthy controls (p<0.001. However, there was no significant decrement in expression of VEGF-A mRNA of AML patients compared to the control group (p=0.861. VEGF-A and VEGF-C expression were not able to predict clinical outcome. CONCLUSION: Our data showed that AML is associated with a decreased expression of VEGF-C mRNA. However, expression levels did not influence the clinical outcome in our study. It seems that angiogenesis is affected by different cytokines other than VEGF-C or VEGF-A, and VEGF is also affected by different cytokines. Taken together, these findings help to provide new insights into the investigation of other angiogenic factors and cytokines that may play roles in the pathogenesis of AML.

  14. Transient Ablation of Teflon Hemispheres

    Arai, Norio; Karashima, Kei-ichi; Sato, Kiyoshi

    1997-01-01

    For high-speed entry of space vehicles into atmospheric environments, ablation is a practical method for alleviating severe aerodynamic heating. Several studies have been undertaken on steady or quasi-steady ablation. However, ablation is a very complicated phenomenon in which a nonequilibrium chemical process is associated with an aerodynamic process that involves changes in body shape with time. Therefore, it seems realistic to consider that ablation is an unsteady phenomenon. In the design of an ablative heat-shield system, since the ultimate purpose of the heat shield is to keep the internal temperature of the space vehicle at a safe level during entry, the transient heat conduction characteristics of the ablator may be critical in the selection of the material and its thickness. This note presents an experimental study of transient ablation of Teflon, with particular emphasis on the change in body shape, the instantaneous internal temperature distribution, and the effect of thermal expansion on ablation rate.

  15. Power Laser Ablation Symposia

    Phipps, Claude

    2007-01-01

    Laser ablation describes the interaction of intense optical fields with matter, in which atoms are selectively driven off by thermal or nonthermal mechanisms. The field of laser ablation physics is advancing so rapidly that its principal results are seen only in specialized journals and conferences. This is the first book that combines the most recent results in this rapidly advancing field with authoritative treatment of laser ablation and its applications, including the physics of high-power laser-matter interaction. Many practical applications exist, ranging from inertial confinement fusion to propulsion of aerostats for pollution monitoring to laser ignition of hypersonic engines to laser cleaning nanoscale contaminants in high-volume computer hard drive manufacture to direct observation of the electronic or dissociative states in atoms and molecules, to studying the properties of materials during 200kbar shocks developed in 200fs. Selecting topics which are representative of such a broad field is difficu...

  16. Thrombospondin-1 and VEGF in inflammatory bowel disease

    Canan Alkim

    2012-01-01

    Full Text Available Angiogenesis is an important process in the pathogenesis of chronic inflammation. We aimed to study the angiogeneic balance in inflammatory bowel disease (IBD by evaluating the expression of vascular endothelial growth factor (VEGF and thrombospondin-1 (TSP-1 on colonic epithelial cells, together with the expression of inducible nitric oxide synthase (iNOS.Twenty-one ulcerative colitis (UC, 14 Crohn's disease (CD, 11 colorectal cancer patients, and 11 healthy controls colonic biopsy samples were evaluated immunohistochemically.The expressions of TSP-1, VEGF, and iNOS in UC and CD groups were higher than expression in healthy control group, all with statistical significance. However, in colorectal cancer group, VEGF and iNOS expressions were increased importantly, but TSP-1 expression was not statistically different from healthy control group's expression. Both TSP-1 and VEGF expressions were correlated with iNOS expression distinctly but did not correlate with each other.Both pro-angiogeneic VEGF and antiangiogeneic TSP-1 expressions were found increased in our IBD groups, but in colorectal cancer group, only VEGF expression was increased. TSP-1 increases in IBD patients as a response to inflammatory condition, but this increase was not enough to suppress pathologic angiogenesis and inflammation in IBD.

  17. Optical-vortex laser ablation

    Hamazaki, Junichi; Morita, Ryuji; Chujo, Keisuke; Kobayashi, Yusuke; Tanda, Satoshi; Omatsu, Takashige

    2010-01-01

    Laser ablation of Ta plates using nanosecond optical vortex pulses was carried out, for the first time. It was suggested that owing to orbital angular momentum of optical vortex, clearer and smoother processed surfaces were obtained with less ablation threshold fluence, in comparison with the ablation by a nonvortex annular beam modified from a spatially Gaussian beam.

  18. Basal and apical regulation of VEGF-A and placenta growth factor in the RPE/choroid and primary RPE

    Kaya, Leyla; Flach, Janina; Lassen, Jens; Treumer, Felix; Roider, Johann

    2015-01-01

    Purpose Members of the vascular endothelial growth factor (VEGF) family are strongly involved in pathological processes in the retina, such as age-related macular degeneration and diabetic retinopathy. Cells of the retinal pigment epithelium (RPE) constitutively secrete VEGF-A, and the secretion of placental growth factor (PlGF) has also been described. RPE cells are strongly polarized cells with different secretome at the apical and basal side. In this study, we evaluated the basal and apical regulation of VEGF-A and PlGF secretion in RPE/choroid explants and primary RPE cells. Methods RPE/choroid tissue explants were prepared from porcine eyes and cultivated in modified Ussing chambers, separating apical (RPE) and basal (choroid) supernatant. Primary RPE cells were also prepared from porcine eyes and cultivated on Transwell plates. Explants and cells were treated with inhibitors for VEGFR-2 (SU1498), p38 (SB203580), and the transcription factors nuclear factor-kappa B (NF-κB) and SP-1 (mithramycin), respectively. VEGF-A and PlGF content was evaluated with enzyme-linked immunosorbent assay (ELISA). In addition, western blots were performed. Results In the RPE/choroid, VEGF-A can initially be found on the apical and basal sides with significantly more pronounced secretion on the basal side. VEGF-A secretion is differentially regulated on the apical and basal sides, with the inhibition of SP-1 and NF-κB showing strong effects apically and basally after 24 h and 48 h, the inhibition of p38 displaying its effect mainly on the basal side with some effect apically after 48 h, and the inhibition of VEGFR-2 reducing the secretion of VEGF only on the apical side at 24 h and 48 h. In the RPE cell culture, similar effects were found, with inhibition of NF-κB or SP-1 displaying a strong decrease in VEGF-A on both sides, and p38 inhibition displaying only an inhibitory effect on the basal side. In contrast, an apical effect of VEGFR-2 inhibition was not found. However, the

  19. DNA methylation regulates expression of VEGF-R2 (KDR) and VEGF-R3 (FLT4)

    Vascular Endothelial Growth Factors (VEGFs) and their receptors (VEGF-Rs) are important regulators for angiogenesis and lymphangiogenesis. VEGFs and VEGF-Rs are not only expressed on endothelial cells but also on various subtypes of solid tumors and leukemias contributing to the growth of the malignant cells. This study was performed to examine whether VEGF-R2 (KDR) and VEGF-R3 (FLT4) are regulated by DNA methylation. Real-time (RT) PCR analysis was performed to quantify KDR and FLT4 expression in some ninety leukemia/lymphoma cell lines, human umbilical vein endothelial cells (HUVECs) and dermal microvascular endothelial cells (HDMECs). Western blot analyses and flow cytometric analyses confirmed results at the protein level. After bisulfite conversion of DNA we determined the methylation status of KDR and FLT4 by DNA sequencing and by methylation specific PCR (MSP). Western blot analyses were performed to examine the effect of VEGF-C on p42/44 MAPK activation. Expression of KDR and FLT4 was observed in cell lines from various leukemic entities, but not in lymphoma cell lines: 16% (10/62) of the leukemia cell lines expressed KDR, 42% (27/65) were FLT4 positive. None of thirty cell lines representing six lymphoma subtypes showed more than marginal expression of KDR or FLT4. Western blot analyses confirmed KDR and FLT4 protein expression in HDMECs, HUVECs and in cell lines with high VEGF-R mRNA levels. Mature VEGF-C induced p42/44 MAPK activation in the KDR- /FLT4+ cell line OCI-AML1 verifying the model character of this cell line for VEGF-C signal transduction studies. Bisulfite sequencing and MSP revealed that GpG islands in the promoter regions of KDR and FLT4 were unmethylated in HUVECs, HDMECs and KDR+ and FLT4+ cell lines, whereas methylated cell lines did not express these genes. In hypermethylated cell lines, KDR and FLT4 were re-inducible by treatment with the DNA demethylating agent 5-Aza-2'deoxycytidine, confirming epigenetic regulation of both genes

  20. VEGF111b, a new member of VEGFxxxb isoforms and induced by mitomycin C, inhibits angiogenesis

    Gu, Fang; Li, Xiuli [Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing (China); Kong, Jian [Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing (China); Pan, Bing [The Institute of Cardiovascular Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Sun, Min [Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, Xian (China); Zheng, Lemin, E-mail: zhengl@bjmu.edu.cn [The Institute of Cardiovascular Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Yao, Yuanqing, E-mail: yqyao@126.com [Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing (China)

    2013-11-08

    Highlights: •We discovered a new member of VEGFxxxb family-VEGF111b. •We found VEGF111b mRNA and protein can be induced by mitomycin C. •We confirmed VEGF111b over-expression inhibits angiogenesis. •VEGF111b inhibits angiogenesis through inhibiting VEGF-R2/PI3K/Akt and VEGF-R2/ERK1/2 phosphorylation. -- Abstract: Vascular endothelial growth factor (VEGF-A) stimulating angiogenesis is required for tumor growth and progression. The conventional VEGF-A isoforms have been considered as pro-angiogenic factors. Another family of VEGF-A isoforms generated by alternative splicing, termed VEGFxxxb isoforms, has anti-angiogenic property, exemplified by VEGF165b. Here, we identify a new number of VEGFxxx family-VEGF111b induced by mitomycin C, although not detected in mitomycin C-unexposed ovarian cancer cells. SKOV3 cells were transfected with pcDNA{sub 3.1} empty vector, pcDNA{sub 3.1}-VEGF111b or pcDNA{sub 3.1}-VEGF165b to collect conditioned mediums respectively. VEGF111b overexpression inhibits proliferation, migration and tube formation of endothelial cell by inhibiting VEGF-R2 phosphorylation and its downstream signaling, similar to VEGF165b but slightly lower than VEGF165b. The anti-angiogenic property depends on the six amino acids of exon 8b of the VEGFxxxb isoforms. Our results show that VEGF111b is a novel potent anti-angiogenic agent that can target the VEGF-R2 and its signaling pathway to inhibit ovarian tumor growth.

  1. VEGF111b, a new member of VEGFxxxb isoforms and induced by mitomycin C, inhibits angiogenesis

    Highlights: •We discovered a new member of VEGFxxxb family-VEGF111b. •We found VEGF111b mRNA and protein can be induced by mitomycin C. •We confirmed VEGF111b over-expression inhibits angiogenesis. •VEGF111b inhibits angiogenesis through inhibiting VEGF-R2/PI3K/Akt and VEGF-R2/ERK1/2 phosphorylation. -- Abstract: Vascular endothelial growth factor (VEGF-A) stimulating angiogenesis is required for tumor growth and progression. The conventional VEGF-A isoforms have been considered as pro-angiogenic factors. Another family of VEGF-A isoforms generated by alternative splicing, termed VEGFxxxb isoforms, has anti-angiogenic property, exemplified by VEGF165b. Here, we identify a new number of VEGFxxx family-VEGF111b induced by mitomycin C, although not detected in mitomycin C-unexposed ovarian cancer cells. SKOV3 cells were transfected with pcDNA3.1 empty vector, pcDNA3.1-VEGF111b or pcDNA3.1-VEGF165b to collect conditioned mediums respectively. VEGF111b overexpression inhibits proliferation, migration and tube formation of endothelial cell by inhibiting VEGF-R2 phosphorylation and its downstream signaling, similar to VEGF165b but slightly lower than VEGF165b. The anti-angiogenic property depends on the six amino acids of exon 8b of the VEGFxxxb isoforms. Our results show that VEGF111b is a novel potent anti-angiogenic agent that can target the VEGF-R2 and its signaling pathway to inhibit ovarian tumor growth

  2. Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis

    Mac Gabhann Feilim

    2011-05-01

    Full Text Available Abstract Background The spatial distribution of vascular endothelial growth factor A (VEGF is an important mediator of vascular patterning. Previous experimental studies in the mouse hindbrain and retina have suggested that VEGF alternative splicing, which controls the ability of VEGF to bind to heparan sulfate proteoglycans (HSPGs in the extracellular matrix (ECM, plays a key role in controlling VEGF diffusion and gradients in tissues. Conversely, proteolysis notably by matrix metalloproteinases (MMPs, plays a critical role in pathological situations by releasing matrix-sequestered VEGF and modulating angiogenesis. However, computational models have predicted that HSPG binding alone does not affect VEGF localization or gradients at steady state. Results Using a 3D molecular-detailed reaction-diffusion model of VEGF ligand-receptor kinetics and transport, we test alternate models of VEGF transport in the extracellular environment surrounding an endothelial sprout. We show that differences in localization between VEGF isoforms, as observed experimentally in the mouse hindbrain, as well as the ability of proteases to redistribute VEGF in pathological situations, are consistent with a model where VEGF is endogenously cleared or degraded in an isoform-specific manner. We use our predictions of the VEGF distribution to quantify a tip cell's receptor binding and gradient sensing capacity. A novel prediction is that neuropilin-1, despite functioning as a coreceptor to VEGF165-VEGFR2 binding, reduces the ability of a cell to gauge the relative steepness of the VEGF distribution. Comparing our model to available in vivo vascular patterning data suggests that vascular phenotypes are most consistently predicted at short range by the soluble fraction of the VEGF distributions, or at longer range by matrix-bound VEGF detected in a filopodia-dependent manner. Conclusions Isoform-specific VEGF degradation provides a possible explanation for numerous examples

  3. Spark ablation device

    Schmidt-Ott, A.; Pfeiffer, T.V.

    2013-01-01

    A spark ablation device for generating nanoparticles comprising a spark generator; the spark generator comprising first and second electrodes, wherein the spark generator further comprises at least one power source which is arranged to be operative at a first energy level for maintaining a discharge

  4. Tumor ablations in IMRI

    Roberto Blanco Sequeiros

    2002-01-01

    @@ IntroductionMagnetic resonance imaging based guidance control and monitoring of minimally invasive intervention has developed from a hypothetical concept to a practical possibility. Magnetic-resonance-guided interstitial therapy in principle is defined as a treatment technique for ablating deepseated tumors in the human body.

  5. Differential regulation of angiogenesis using degradable VEGF-binding microspheres.

    Belair, David G; Miller, Michael J; Wang, Shoujian; Darjatmoko, Soesiawati R; Binder, Bernard Y K; Sheibani, Nader; Murphy, William L

    2016-07-01

    Vascular endothelial growth factor (VEGF) spatial and temporal activity must be tightly controlled during angiogenesis to form perfusable vasculature in a healing wound. The native extracellular matrix (ECM) regulates growth factor activity locally via sequestering, and researchers have used ECM-mimicking approaches to regulate the activity of VEGF in cell culture and in vivo. However, the impact of dynamic, affinity-mediated growth factor sequestering has not been explored in detail with biomaterials. Here, we sought to modulate VEGF activity dynamically over time using poly(ethylene glycol) microspheres containing VEGF-binding peptides (VBPs) and exhibiting varying degradation rates. The degradation rate of VBP microspheres conferred a differential ability to up- or down-regulate VEGF activity in culture with primary human endothelial cells. VBP microspheres with fast-degrading crosslinks reduced VEGF activity and signaling, while VBP microspheres with no inherent degradability sequestered and promoted VEGF activity in culture with endothelial cells. VBP microspheres with degradable crosslinks significantly reduced neovascularization in vivo, but neither non-degradable VBP microspheres nor bolus delivery of soluble VBP reduced neovascularization. The covalent incorporation of VBP to degradable microspheres was required to reduce neovascularization in a mouse model of choroidal neovascularization in vivo, which demonstrates a potential clinical application of degradable VBP microspheres to reduce pathological angiogenesis. The results herein highlight the ability to modulate the activity of a sequestered growth factor by changing the crosslinker identity within PEG hydrogel microspheres. The insights gained here may instruct the design and translation of affinity-based growth factor sequestering biomaterials for regenerative medicine applications. PMID:27061268

  6. SREBP inhibits VEGF expression in human smooth muscle cells

    Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs

  7. Anti-VEGF Agents for Ocular Angiogenesis and Vascular Permeability

    Kenichi Kimoto

    2012-01-01

    Full Text Available We review articles describing intravitreal injection of anti-VEGF drug trials, while discussing the mechanisms of the action of anti-VEGF antibodies, and also evaluating their outcomes. Intraocular injections of anti-VEGF drug are considered to be an effective treatment for macular edema after retinal vein occlusion, however, recurrent/persistent edema is common. The recent reports may lead to a shift in treatment paradigm for DME, from laser photocoagulation, to newer approaches using anti-VEGF drugs. There have been several well-publicized prospective, randomized studies that demonstrated the efficacy of intravitreal injection of anti-VEGF drugs for patients with AMD. Adjuvant bevacizumab for neovascular glaucoma may prevent further PAS formation, and it is likely to open up a therapeutic window for a panretinal photocoagulation and trabeculectomy. Intravitreal injection of bevacizumab (IVB results in a substantial decrease in bleeding from the retinal vessels or new vessels during a standard vitrectomy. IVB has also been reported to be effective for inducing the regression of new vessels in proliferative diabetic retinopathy. The use of bevacizumab in stage 4 or 5 retinopahty of permaturity (ROP is to reduce the plus sign to help reduce hemorrhage during the subsequent vitrectomy. Some authors reported cases of resolution of stage 4 A ROP after bevacizumab injection.

  8. DNA methylation regulates expression of VEGF-C, and S-adenosylmethionine is effective for VEGF-C methylation and for inhibiting cancer growth

    DNA hypomethylation may activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-adenosylmethionine (SAM) is a methyl donor in numerous methylation reactions and acts as an inhibitor of intracellular demethylase activity, which results in hypermethylation of DNA. The main objectives of this study were to determine whether DNA hypomethylation correlated with vascular endothelial growth factor-C (VEGF-C) expression, and the effect of SAM on VEGF-C methylation and gastric cancer growth inhibition. VEGF-C expression was assayed by Western blotting and RT-qPCR in gastric cancer cells, and by immunohistochemistry in tumor xenografts. VEGF-C methylation was assayed by bisulfite DNA sequencing. The effect of SAM on cell apoptosis was assayed by flow cytometry analyses and its effect on cancer growth was assessed in nude mice. The VEGF-C promoters of MGC-803, BGC-823, and SGC-7901 gastric cancer cells, which normally express VEGF-C, were nearly unmethylated. After SAM treatment, the VEGF-C promoters in these cells were highly methylated and VEGF-C expression was downregulated. SAM also significantly inhibited tumor growth in vitro and in vivo. DNA methylation regulates expression of VEGF-C. SAM can effectively induce VEGF-C methylation, reduce the expression of VEGF-C, and inhibit tumor growth. SAM has potential as a drug therapy to silence oncogenes and block the progression of gastric cancer

  9. DNA methylation regulates expression of VEGF-C, and S-adenosylmethionine is effective for VEGF-C methylation and for inhibiting cancer growth

    Da, M.X. [Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou (China); Zhang, Y.B. [Department of Surgery, Ningxia Medical University, Yinchuan (China); Yao, J.B. [Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou (China); Duan, Y.X. [Department of Surgery, Ningxia Medical University, Yinchuan (China)

    2014-09-30

    DNA hypomethylation may activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-adenosylmethionine (SAM) is a methyl donor in numerous methylation reactions and acts as an inhibitor of intracellular demethylase activity, which results in hypermethylation of DNA. The main objectives of this study were to determine whether DNA hypomethylation correlated with vascular endothelial growth factor-C (VEGF-C) expression, and the effect of SAM on VEGF-C methylation and gastric cancer growth inhibition. VEGF-C expression was assayed by Western blotting and RT-qPCR in gastric cancer cells, and by immunohistochemistry in tumor xenografts. VEGF-C methylation was assayed by bisulfite DNA sequencing. The effect of SAM on cell apoptosis was assayed by flow cytometry analyses and its effect on cancer growth was assessed in nude mice. The VEGF-C promoters of MGC-803, BGC-823, and SGC-7901 gastric cancer cells, which normally express VEGF-C, were nearly unmethylated. After SAM treatment, the VEGF-C promoters in these cells were highly methylated and VEGF-C expression was downregulated. SAM also significantly inhibited tumor growth in vitro and in vivo. DNA methylation regulates expression of VEGF-C. SAM can effectively induce VEGF-C methylation, reduce the expression of VEGF-C, and inhibit tumor growth. SAM has potential as a drug therapy to silence oncogenes and block the progression of gastric cancer.

  10. Intracellular autocrine VEGF signaling promotes EBDC cell proliferation, which can be inhibited by Apatinib.

    Peng, Sui; Zhang, Yanyan; Peng, Hong; Ke, Zunfu; Xu, Lixia; Su, Tianhong; Tsung, Allan; Tohme, Samer; Huang, Hai; Zhang, Qiuyang; Lencioni, Riccardo; Zeng, Zhirong; Peng, Baogang; Chen, Minhu; Kuang, Ming

    2016-04-10

    Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC. PMID:26805764

  11. Meteoroid ablation models

    Popova, Olga

    2004-12-01

    The fate of entering meteoroids in atmosphere is determined by their size, velocity and substance properties. Material from ablation of small-sized meteors (roughly R≤0.01-1 cm) is mostly deposited between 120 and 80 km altitudes. Larger bodies (up to meter sizes) penetrate deeper into the atmosphere (down to 20 km altitude). Meteoroids of cometary origin typically have higher termination altitude due to substance properties and higher entry velocity. Fast meteoroids ( V>30-40 km/s) may lose a part of their material at higher altitudes due to sputtering. Local flow regime realized around the falling body determines the heat transfer and mass loss processes. Classic approach to meteor interaction with atmosphere allows describing two limiting cases: - large meteoroid at relatively low altitude, where shock wave is formed (hydrodynamical models); - small meteoroid/or high altitudes - free molecule regime of interaction, which assumes no collisions between evaporated meteoroid particles. These evaporated particles form initial train, which then spreads into an ambient air due to diffusion. Ablation models should make it possible to describe physical conditions that occur around meteor body. Several self-consistent hydrodynamical models are developed, but similar models for transition and free molecule regimes are still under study. This paper reviews existing ablation models and discusses model boundaries.

  12. Notch, IL-1 and leptin crosstalk outcome (NILCO is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer.

    Shanchun Guo

    Full Text Available High levels of pro-angiogenic factors, leptin, IL-1, Notch and VEGF (ligands and receptors, are found in breast cancer, which is commonly correlated with metastasis and lower survival of patients. We have previously reported that leptin induces the growth of breast cancer and the expression of VEGF/VEGFR-2 and IL-1 system. We hypothesized that Notch, IL-1 and leptin crosstalk outcome (NILCO plays an essential role in the regulation of leptin-mediated induction of proliferation/migration and expression of pro-angiogenic molecules in breast cancer. To test this hypothesis, leptin's effects on the expression and activation of Notch signaling pathway and VEGF/VEGFR-2/IL-1 were determined in mouse (4T1, EMT6 and MMT breast cancer cells. Remarkably, leptin up-regulated Notch1-4/JAG1/Dll-4, Notch target genes: Hey2 and survivin, together with IL-1 and VEGF/VEGFR-2. RNA knockdown and pharmacological inhibitors of leptin signaling significantly abrogated activity of reporter gene-luciferase CSL (RBP-Jk promoter, showing that it was linked to leptin-activated JAK2/STAT3, MAPK, PI-3K/mTOR, p38 and JNK signaling pathways. Interestingly, leptin upregulatory effects on cell proliferation/migration and pro-angiogenic factors Notch, IL-1 and VEGF/VEGFR-2 were abrogated by a γ-secretase inhibitor, DAPT, as well as siRNA against CSL. In addition, blockade of IL-1R tI inhibited leptin-induced Notch, Hey2 and survivin as well as VEGF/VEGFR-2 expression. These data suggest leptin is an inducer of Notch (expression/activation and IL-1 signaling modulates leptin effects on Notch and VEGF/VEGFR-2. We show for the first time that a novel unveiled crosstalk between Notch, IL-1 and leptin (NILCO occurs in breast cancer. Leptin induction of proliferation/migration and upregulation of VEGF/VEGFR-2 in breast cancer cells were related to an intact Notch signaling axis. NILCO could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals

  13. Insight into 144 patients with ocular vascular events during VEGF antagonist injections

    Mansour, Ahmad M; Shahin, Maha; Kofoed, Peter K;

    2012-01-01

    To record ocular vascular events following injections of vascular endothelium growth factor (VEGF) antagonists.......To record ocular vascular events following injections of vascular endothelium growth factor (VEGF) antagonists....

  14. Recombinant Goat VEGF164 Increases Hair Growth by Painting Process on the Skin of Shaved Mouse.

    Bao, Wenlei; Yin, Jianxin; Liang, Yan; Guo, Zhixin; Wang, Yanfeng; Liu, Dongjun; Wang, Xiao; Wang, Zhigang

    2014-09-01

    To detect goat vascular endothelial growth factor (VEGF)-mediated regrowth of hair, full-length VEGF164 cDNA was cloned from Inner Mongolia cashmere goat (Capra hircus) into the pET-his prokaryotic expression vector, and the recombinant plasmid was transferred into E. coli BL21 cells. The expression of recombinant 6×his-gVEGF164 protein was induced by 0.5 mM isopropyl thio-β-D-galactoside at 32°C. Recombinant goat VEGF164 (rgVEGF164) was purified and identi ed by western blot using monoclonal anti-his and anti-VEGF antibodies. The rgVEGF164 was smeared onto the dorsal area of a shaved mouse, and we noted that hair regrowth in this area was faster than in the control group. Thus, rgVEGF164 increases hair growth in mice. PMID:25178380

  15. Bone and Soft Tissue Ablation

    Foster, Ryan C.B.; Joseph M Stavas

    2014-01-01

    Bone and soft tissue tumor ablation has reached widespread acceptance in the locoregional treatment of various benign and malignant musculoskeletal (MSK) lesions. Many principles of ablation learned elsewhere in the body are easily adapted to the MSK system, particularly the various technical aspects of probe/antenna design, tumoricidal effects, selection of image guidance, and methods to reduce complications. Despite the common use of thermal and chemical ablation procedures in bone and soft...

  16. Vascular endothelial growth factor A (VEGF-A) decreases expression and secretion of pleiotrophin in a VEGF receptor-independent manner.

    Poimenidi, Evangelia; Theodoropoulou, Christina; Koutsioumpa, Marina; Skondra, Lamprini; Droggiti, Eirini; van den Broek, Marloes; Koolwijk, Pieter; Papadimitriou, Evangelia

    2016-05-01

    Vascular endothelial growth factor A (VEGF-A) is a key molecule in angiogenesis acting through VEGF receptors (VEGFRs), ανβ3 integrin, receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and cell surface nucleolin (NCL). Pleiotrophin (PTN) stimulates endothelial cell migration and limits the angiogenic effects of VEGF-A165 to the levels of its own effect, possibly acting as a VEGF-A165 modifier. Since PTN and VEGF-A165 share receptors and actions on endothelial cells, in the present work we studied whether and how VEGF-A165 affects PTN expression or secretion. VEGF-A165 decreased PTN mRNA and protein levels acting at the transcriptional level. Bevacizumab, a selective VEGFR2 tyrosine kinase inhibitor and down-regulation of VEGFR2 expression by siRNA did not affect this decrease, suggesting that it is VEGFR-independent. VEGF-A121 also decreased PTN mRNA and protein levels, suggesting that heparin binding of VEGF-A165 is not involved. Blockage of cell surface NCL, lack of expression or mutation of β3 integrin and down-regulation of RPTPβ/ζ abolished the inhibitory effect of VEGF-A165 on PTN expression and secretion. Down-regulation of endogenous PTN in endothelial cells enhanced VEGF-A165-induced increase in migration and tube formation on matrigel. Collectively, these data suggest that VEGF-A down-regulates PTN expression and secretion through the RPTPβ/ζ-ανβ3-NCL axis to enhance its own effect on cell migration and further highlight the role of RPTPβ/ζ in VEGF-A actions. PMID:26924457

  17. Ablation Plume Induced by Laser Euv Radiation

    Frolov, Oleksandr; Koláček, Karel; Schmidt, Jiří; Štraus, Jaroslav

    Dordrecht: Springer International Publishing, 2015 - (Rocca, J.; Menoni, C.; Marconi, M.), s. 397-403. (Springer Proceedings in Physics. 169). ISBN 978-3-319-19521-6. [International Conference on X-Ray Laser s/14./. Fort Collins, Colorado (US), 26.05.2014-30.05.2014] R&D Projects: GA ČR(CZ) GA14-29772S; GA MŠk(CZ) LG13029 Institutional support: RVO:61389021 Keywords : EUV laser * laser ablation * plume * Au * Al * Si * Cu * energy measurements Subject RIV: BL - Plasma and Gas Discharge Physics http://link.springer.com/chapter/10.1007/978-3-319-19521-6_52

  18. The biophysical property of A549 cells transferred by VEGF-D.

    Wang, Zhen; Wu, Xiu-Li; Wang, Xu; Tian, Hong-Xia; Chen, Zhi-Hong; Li, Yang-Qiu

    2014-01-01

    Vascular endothelial growth factor-D (VEGF-D) together with VEGF-C is considered to be associated with lymphangiogenesis and angiogenesis and involve in tumorization. This study aims to investigate the influence of exogenous VEGF-D gene on the biophysical property of cell surface of lung adenocarcinoma cell line. A panel of lung adenocarcinoma cell lines were examined the expression of VEGF-D and VEGF-C by real-time PCR. The VEGF-D recombinant plasmid containing enhanced green fluorescence protein (EGFP) was constructed and transfected to the cell line with no expression of VEGF-D and confirmed by real-time PCR and Western blot analysis. Topographic images of cells were obtained by using atomic force microscope (AFM) in contact mode. Unlike VEGF-C, VEGF-D was found to have a very low expression or undetectable expression in lung adenocarcinoma cell lines. The VEGF-D recombinant plasmid had been constructed successfully and was transferred into the human lung adenocarcinoma cell line A549 cells which had no endogenous expression of VEGF-D, and exogenous VEGF-D could be detected in mRNA and protein expression levels in the gene modified cells, while the VEGF-C gene expression had no change after VEGF-D transfection. After transfection, the irregular microspikes or nano clusters could observe on the surface of A549 cells, and VEGF-D transfected A549 cells became more rigid. The exogenous VEGF-D gene might cause the remarkable biophysical architectural changes in the A549 cells, which might as a novel biomarker for evaluation of its biological function. PMID:23526563

  19. VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema

    Yoon, Young-sup; Murayama, Toshinori; Gravereaux, Edwin; Tkebuchava, Tengiz; Silver, Marcy; Curry, Cynthia; Wecker, Andrea; Kirchmair, Rudolf; Hu, Chun Song; Kearney, Marianne; Ashare, Alan; Jackson, David G.; Kubo, Hajime; Isner, Jeffrey M.; Losordo, Douglas W.

    2003-01-01

    Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C–induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphed...

  20. Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice

    Jo, D.H.; Park, S W; Cho, C S; Powner, M. B.; Fruttiger, M; Kim, J. H.

    2015-01-01

    Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF an...

  1. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade

    Huang, Jianzhong; Bae, Jae-O; Tsai, Judy P.; Kadenhe-Chiweshe, Angela; Papa, Joey; Lee, Alice; Zeng, Shan; Kornfeld, Z. Noah; Ullner, Paivi; Zaghloul, Nibal; Ioffe, Ella; Nandor, Sarah; Burova, Elena; Holash, Jocelyn; Thurston, Gavin

    2009-01-01

    Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signali...

  2. Endoscopic ultrasound guided radiofrequency ablation in pancreas

    Seicean, Andrada; Tefas, Cristian; Ungureanu, Bogdan;

    2014-01-01

    Radiofrequency ablation of the pancreas represents a more effective tumor-destruction method compared to other ablation techniques. The endoscopic ultrasound guided radiofrequency ablation is indicated for locally advanced, non-metastatic pancreatic adenocarcinoma, without the need of general...

  3. The role of VEGF pathways in human physiologic and pathologic angiogenesis.

    In pre-clinical models VEGF is a potent stimulant of both physiologic and pathologic angiogenesis. Conversely, anti-VEGF regimens have successfully inhibited angiogenesis both in vitro and in vivo. We hypothesized that VEGF would stimulate both physiologic and pathologic angiogenesis in a human-ba...

  4. Biological variations in plasma VEGF and VEGFR-1 may compromise their biomarker value in colorectal cancer

    Svendsen, Mads N.; Brunner, Nils; Christensen, Ib Jarle; Ytting, Henriette; Bentsen, Camilla; Lomholt, Anne F.; Nielsen, Hans J.

    2010-01-01

    Vascular Endothelial Growth Factor (VEGF) plays a prominent role in tumor angiogenesis and plasma VEGF concentration may carry prognostic information in colorectal cancer. The VEGF receptor 1 (VEGFR-1) is a regulatory receptor which is shredded into plasma of patients with colorectal cancer. For ...

  5. Elevated expressions of Survivin and VEGF proteins are strong independent predictors of survival in squamous carcinoma of larynx%凋亡抑制蛋白Survivin和血管内皮生长因子高表达是喉鳞状细胞癌生存预后的独立预测因子

    Rong Luo; Weijia Kong; Yanjun Wang

    2008-01-01

    Objective: To study the relationship between Survivin and VEGF proteins in a subgroup of patients with squamous carcinoma of larynx. Methods: 108 cases of squamous carcinoma of larynx with clinical data were collected and expressions of Survivin and VEGF in peripheral blood were investigated by enzyme-linked immunosorbent assay (ELISA). Results: Expressions of Survivin and VEGF were significantly associated with T stage, N stage and metastasis of squamous carcinoma of larynx. The patients with Survivin or VEGF over-expressions presented lower survival rate, respectively, as compared to those of low-expression (P < 0.05). The survival rate in squamous carcinoma of larynx patients with Survivin and VEGF dual over-expressions was significantly lower than that of patients with dual low-expression (P < 0.05). Multivariate analysis indicated that both Survivin and VEGF over-expressions in squamous carcinoma of larynx peripheral blood samples were strong independent factors of poor prognosis in squamous carcinoma of larynx patients. Conclusion: Survivin and VEGF over-expressions are independent prognostic factors for the patients with squamous carcinoma of larynx. These results also suggest that peripheral blood Survivin and VEGF expressions are valuable prognostic markers for prognosis prediction in squamous carcinoma of larynx patients.

  6. Effects of Rosuvastatin and MiR-126 on Myocardial Injury Induced by Acute Myocardial Infarction in Rats: Role of Vascular Endothelial Growth Factor A (VEGF-A).

    Fei, Ling; Zhang, Jun; Niu, Heping; Yuan, Chen; Ma, Xiaoli

    2016-01-01

    BACKGROUND The present study investigated the effects of VEGF-A targeted by miR-126 on myocardial injury after acute myocardial infarction (AMI) in rats, along with the contributions of rosuvastatin to the synergic effect. MATERIAL AND METHODS SD rats were obtained to construct AMI models by ligating their left anterior descending coronary arteries (LAD). We conducted echocardiography to check the 6 involved indexes: left ventricular ejection fractions (LVEF), fractional shortening (FS), left ventricular end-systolic volume (LVV), left ventricular end-diastolic volume (LVVd), cardiac output (CO), and heart rate (HR). Moreover, antibody sandwich enzyme-linked immunosorbent assay was carried out to determine MI markers: creatine kinase (CK), CK Isoenzyme (CK-MB), and Troponin I (cTn I). Dual-Luciferase Reporter Assay was performed to confirm the targeting of miR-126 and VEGF-A. MTT assay provided insight into the proliferation of myocardial fibroblasts. Finally, RT-RCR and Western blot were used for the detection of miR-126 and VEGF-A expressions in vivo and in vitro. RESULTS Luciferase activity assay showed that miR-126 transfection significantly decreased the relative luciferase activity in HEK293T cells when it was bound to normal 3' UTR of VEGF-A (P<0.05). In comparison to the control group, rats in the AMI model group had significantly lower LVEF, FS, and CO, and substantially higher LVVs, LVVd, HR, CK/U, CK-MB/U, and cTn-1/U (all P<0.05). Down-regulated miR-126 and up-regulated VEGF-A were also observed in MI models (P<0.05). CONCLUSIONS miR-126 and rosuvastatin have protective effects on AMI risk, and VEGF-A antagonizes effects on AMI is imposed by. PMID:27376405

  7. Anti-VEGF for the Management of Diabetic Macular Edema

    Francisco Rosa Stefanini

    2014-01-01

    Full Text Available Diabetic retinopathy (DR is an important cause of vision loss around the world, being the leading cause in the population between 20 and 60 years old. Among patients with DR, diabetic macular edema (DME is the most frequent cause of vision impairment and represents a significant public health issue. Macular photocoagulation has been the standard treatment for this condition reducing the risk of moderate visual loss by approximately 50%. The role of vascular endothelial growth factor (VEGF in DR and DME pathogenesis has been demonstrated in recent studies. This review addresses and summarizes data from the clinical trials that investigated anti-VEGF for the management of DME and evaluates their impact on clinical practice. The literature searches were conducted between August and October 2013 in PubMed and Cochrane Library with no date restrictions and went through the most relevant studies on pegaptanib, ranibizumab, bevacizumab, and aflibercept for the management of DME. The efficacy and safety of intravitreal anti-VEGF as therapy for DME have recently been proved by various clinical trials providing significantly positive visual and anatomical results. Regarding clinical practice, those outcomes have placed intravitreal injection of anti-VEGF as an option that must be considered for the treatment of DME.

  8. Heparin desulfation modulates VEGF release and angiogenesis in diabetic wounds.

    Freudenberg, Uwe; Zieris, Andrea; Chwalek, Karolina; Tsurkan, Mikhail V; Maitz, Manfred F; Atallah, Passant; Levental, Kandice R; Eming, Sabine A; Werner, Carsten

    2015-12-28

    While vascular endothelial growth factor (VEGF) has been shown to be one of the key players in wound healing by promoting angiogenesis current clinical applications of this growth factor to the wound environment are poorly controlled and not sustainable. Hydrogels made of sulfated glycosaminoglycans (GAG) allow for the sustained release of growth factors since GAGs engage in electrostatic complexation of biomolecules. In here, we explore a set of hydrogels formed of selectively desulfated heparin derivatives and star-shaped poly(ethylene glycol) with respect to VEGF binding and release and anticoagulant activity. As a proof of concept, supportive effects on migration and tube formation of human umbilical vein endothelial cells were studied in vitro and the promotion of wound healing was followed in genetically diabetic (db/db) mice. Our data demonstrate that the release of VEGF from the hydrogels is modulated in dependence on the GAG sulfation pattern. Hydrogels with low sulfate content (11% of initial heparin) were found to be superior in efficacy of VEGF administration, low anticoagulant activity and promotion of angiogenesis. PMID:26478015

  9. LASER ABLATION STUDIES OF CONCRETE

    Laser ablation was studied as a means of removing radioactive contaminants from the surface and near-surface regions of concrete. We present the results of ablation tests on cement and concrete samples using a 1.6 kW pulsed Nd:YAG laser with fiber optic beam delivery. The laser-s...

  10. Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2

    Compelling evidence suggest that vascular endothelial growth factor (VEGF) and its receptors, especially receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in angiogenesis under both physiological and pathological conditions, including cancer and angiogenic retinopathies such as age-related macular degeneration (AMD). To this end, inhibition of angiogenesis with antagonists to either VEGF or KDR has yielded significant therapeutic efficacy both in preclinical studies in animal models and in clinical trials in patients with cancer and AMD. We previously reported the identification of a high affinity, fully human anti-KDR antibody fragment, 1121B Fab, through a highly stringent affinity maturation process with a Fab originally isolated from a naive human antibody phage display library. In this study, we demonstrate that 1121B Fab is able to strongly block KDR/VEGF interaction, resulting in potent inhibition of an array of biological activities of VEGF, including activation of the receptor and its signaling pathway, intracellular calcium mobilization, and migration and proliferation of endothelial cells. Taken together, our data lend strong support to the further development of 1121B Fab fragment as an anti-angiogenesis agent in both cancer and angiogenic retinopathies

  11. Recombinant Goat VEGF164 Increases Hair Growth by Painting Process on the Skin of Shaved Mouse

    Bao, Wenlei; Yin, Jianxin; Liang, Yan; Guo, Zhixin; Wang, Yanfeng; Liu, Dongjun; Wang, Xiao; Wang, Zhigang

    2014-01-01

    To detect goat vascular endothelial growth factor (VEGF)-mediated regrowth of hair, full-length VEGF164 cDNA was cloned from Inner Mongolia cashmere goat (Capra hircus) into the pET-his prokaryotic expression vector, and the recombinant plasmid was transferred into E. coli BL21 cells. The expression of recombinant 6×his-gVEGF164 protein was induced by 0.5 mM isopropyl thio-β-D-galactoside at 32°C. Recombinant goat VEGF164 (rgVEGF164) was purified and identi ed by western blot using monoclonal...

  12. Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure

    Sun, Kai; Kusminski, Christine M; Luby-Phelps, Kate; Spurgin, Stephen B.; An, Yu A.; Wang, Qiong A; Holland, William L.; Scherer, Philipp E.

    2014-01-01

    We recently reported that local overexpression of VEGF-A in white adipose tissue (WAT) protects against diet-induced obesity and metabolic dysfunction. The observation that VEGF-A induces a “brown adipose tissue (BAT)-like” phenotype in WAT prompted us to further explore the direct function of VEGF-A in BAT. We utilized a doxycycline (Dox)-inducible, brown adipocyte-specific VEGF-A transgenic overexpression model to assess direct effects of VEGF-A in BAT in vivo. We observed that BAT-specific...

  13. Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma

    Andersen, Niels F; Vogel, Ulla; Klausen, Tobias W;

    2012-01-01

    Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor. Several single nucleotide polymorphisms (SNPs) in the VEGF gene with influence on VEGF expression have been described. In multiple myeloma, VEGF stimulates angiogenesis which is correlated with disease progression and pro...... polymorphisms, so in the future we may be able to select multiple myeloma patients who especially will benefit from treatment with thalidomide....... prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide...

  14. Bevacizumab (Avastin) conjugated microbubbles for anti-VEGF treatment of neovascular age-related macular degeneration

    Zhang, Leilei; Xu, Jeff; Huang, Jiwei; Roberts, Cynthia; Xu, Ronald

    2010-02-01

    Bevacizumab (Avastin) has been used as one of the anti-VEGF therapies to manage neovascular age-related macular degeneration (AMD). The drug delivery system for bevacizumab needs to be improved in order to decrease the frequency of injection and reduce the adverse effects. In our study, bevacizumab was conjugated with poly (lactic-co-glycolic acid) (PLGA) microbubbles by activating carboxyl functional groups. The averaged size of microbubbles was estimated 1.055+/-0.258μm, allowing for ultrasound guided drug delivery. The binding efficiency between bevacizumab and microbubbles was evaluated in an enzyme-linked immunosorbent assay plate. The test results demonstrated the potential of using PLGA microbubbles to deliver bevacizumab with imaging guidance.

  15. The interaction of heparan sulfate proteoglycans with endothelial transglutaminase-2 limits VEGF165-induced angiogenesis.

    Beckouche, Nathan; Bignon, Marine; Lelarge, Virginie; Mathivet, Thomas; Pichol-Thievend, Cathy; Berndt, Sarah; Hardouin, Julie; Garand, Marion; Ardidie-Robouant, Corinne; Barret, Alain; Melino, Gerry; Lortat-Jacob, Hugues; Muller, Laurent; Monnot, Catherine; Germain, Stephane

    2015-07-14

    Sprouting angiogenesis is stimulated by vascular endothelial growth factor (VEGF165) that is localized in the extracellular matrix (ECM) and binds to heparan sulfate (HS)-bearing proteins known as heparan sulfate proteoglycans (HSPGs). VEGF165 presentation by HSPGs enhances VEGF receptor-2 (VEGFR2) signaling. We investigated the effect of TG2, which binds to HSPGs, on the interaction between VEGF165 and HS and angiogenesis. Mice with tg2 deficiency showed transiently enhanced retina vessel formation and increased vascularization of VEGF165-containing Matrigel implants. In addition, endothelial cells in which TG2 was knocked down exhibited enhanced VEGF165-induced sprouting and migration, which was associated with increased phosphorylation of VEGFR2 at Tyr(951) and its targets Src and Akt. TG2 knockdown did not affect the phosphorylation of VEGFR2 at Tyr(1175) or cell proliferation in response to VEGF165 and sprouting or signaling in response to VEGF121. Decreased phosphorylation of VEGFR2 at Tyr(951) was due to ECM-localized TG2, which reduced the binding of VEGF165 to endothelial ECM in a manner that required its ability to bind to HS but not its catalytic activity. Surface plasmon resonance assays demonstrated that TG2 impeded the interaction between VEGF165 and HS. These results show that TG2 controls the formation of VEGF165-HSPG complexes and suggest that this regulation could be pharmacologically targeted to modulate developmental and therapeutic angiogenesis. PMID:26175493

  16. The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy.

    Carter, James G; Gammons, Melissa V R; Damodaran, Gopinath; Churchill, Amanda J; Harper, Steven J; Bates, David O

    2015-01-01

    Anti-VEGF-A therapy has become a mainstay of treatment for ocular neovascularisation and in cancer; however, their effectiveness is not universal, in some cases only benefiting a minority of patients. Anti-VEGF-A therapies bind and block both pro-angiogenic VEGF-Axxx and the partial agonist VEGF-Axxxb isoforms, but their anti-angiogenic benefit only comes about from targeting the pro-angiogenic isoforms. Therefore, antibodies that exclusively target the pro-angiogenic isoforms may be more effective. To determine whether C-terminal-targeted antibodies could inhibit angiogenesis, we generated a polyclonal antibody to the last nine amino acids of VEGF-A165 and tested it in vitro and in vivo. The exon8a polyclonal antibody (Exon8apab) did not bind VEGF-A165b even at greater than 100-fold excess concentration, and dose dependently inhibited VEGF-A165 induced endothelial migration in vitro at concentrations similar to the VEGF-A antibody fragment ranibizumab. Exon8apab can inhibit tumour growth of LS174t cells implanted in vivo and blood vessel growth in the eye in models of age-related macular degeneration, with equal efficacy to non-selective anti-VEGF-A antibodies. It also showed that it was the VEGF-Axxx levels specifically that were upregulated in plasma from patients with proliferative diabetic retinopathy. These results suggest that VEGF-A165-specific antibodies can be therapeutically useful. PMID:25274272

  17. Transcriptional regulation of the VEGF gene in dependence of individual genomic variations.

    Metzger, Carmen S; Koutsimpelas, Dimitrios; Brieger, Juergen

    2015-12-01

    Overexpression of the vascular endothelial growth factor (VEGF) gene has been associated with advanced stage and poor survival in several cancers. The majority of disease-associated VEGF-single nucleotide polymorphisms (SNPs) locate within regulatory regions. Therefore, an influence of SNPs located in the promoter/5'-untranslated region (5'UTR) on transcription factor binding (TFB) and gene expression seems feasible. We reviewed the literature investigating a potential connection of VEGF-SNPs and transcriptional regulation of the VEGF gene. In addition, we employed transcription factor databases to search for VEGF-SNPs which have already been associated with diseases. The objective of this review is to gain an overview about an association of VEGF-SNPs and the transcription factor dependent regulation of the VEGF gene. A decreasing binding specificity of the transcription factor MZF1 in presence of the VEGF-SNP +405 C-allele has been reported. TF databases indicated a potential HIF binding site for the -2578 C-allele representing an important potential inducer of VEGF expression. Additionally, linkage disequilibrium of the -2578 A-allele and an 18 bp insertion increases the number of potential TFB sites. For the VEGF promoter SNP -1154 A/G an interaction with the HRE under participation of the SNP +405 C/G was supposed. The comprehension of the association of specific SNPs and TFB could be an essential part in our understanding of individual differences of VEGF regulation and course of diseases. PMID:26209503

  18. Cancer-derived VEGF plays no role in malignant ascites formation in the mouse

    Bayasi Guleng; Tsuneo Ikenoue; Yasushi Fukushima; Keita Morikane; Makoto Miyagishi; Kazunari Taira; Takao Kawabe; Masao Omata; Keisuke Tateishi; Fumihiko Kanai; Amarsanaa Jazag; Miki Ohta; Yoshinari Asaoka; Hideaki Ijichi; Yasuo Tanaka; Jun Imamura

    2005-01-01

    AIM: Vascular endothelial growth factor (VEGF) is a potent mediator of peritoneal fluid accumulation following tumor progression. This study investigated the role of VEGF secreted by cancerous cells in the formation of malignant ascites.METHODS: VEGF expression was eliminated byknockdown in the pancreas cancer cell-line PancO2 using vector-based short-hairpin type RNA interference (RNAi).Malignant ascites formation in the mouse was analyzed by intraperitoneal injection of PancO2 cells expressing VEGF or with expression knockdown.RESULTS: The VEGF knockdown PancO2 cell was successfully established. Knockdown of VEGF did not affect cancer cell proliferation in vitro or in vivo. The volume of ascites following peritoneal expansion of the tumor in VEGF knockdown cells and control cells did not differ statistically in this in vivo study. Moreover, the VEGF concentration in the ascites did not differ statistically.CONCLUSION: Malignant ascites formation might be mediated by VEGF production in noncancerous tissues,such as stromal compartments. An anti-VEGF strategy against malignant ascites could be applied to various tumors regardless of whether they secrete VEGF.

  19. The VEGF system and tie-2 are spatio-temporal expressed during tayassu placentation

    Miglino, M.A.; Santos, T.C.; Papa, P.C.;

    Objectives: The vascular endothelial growth factor (VEGF) is one of the most important vascular mitogens, while the angiotensin receptor Tie-2 binds to the angiopoietin and stabilizes newly formed vessels. We therefore wanted to localize VEGF and its receptors VEGF-R1, VEGF-R2 and the Tie-2...... for immunhistochemistry using polyclonal antibodies against VEGF, VEGFR-1, VEGFR-2 and Tie-2. Results: In the present study the VEGF-system exhibited intense staining in the uterine epithelium, uterine glandular epithelium and trophoblast. The endothelial cells and smooth muscle cells of the vessels...... in the maternal and fetal compartment were also immunoreactive. Placentae from initial phase of gestation showed weaker staining when compared to middle and late gestation. In late gestation of the tayassu the Tie-2 was co-localized with the VEGF-system in both maternal (intense staining in glandular...

  20. The expression and function of VEGF at embryo implanta- tion "window" in the mouse

    2001-01-01

    Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that plays a critical role in angiogenesis. Recent reports indicated that VEGF was closely involved in embryo implantation and embryonic vasculogenesis. However, very little information is available about the detailed expression and function of VEGF at implantation "window". In this work, VEGFs were primarily present on uterine epithelial cell monolayer and blastocysts including the outgrew trophoblasts at implantation window. VEGF antibodies decreased the number of mice embryos implanted and the percentage of blastocysts with attachment and outgrowth in a co-culture model in a dose-dependant manner. These findings demonstrate that VEGF is one of the essential cytokines for embryo implantation in mouse. VEGF may act as a local mediator to regulate the maternal-fetal interaction, and facilitate blastocyst implantation.

  1. EUV ablation of organic polymers at a high fluence

    Chiara; Liberatore; Klaus; Mann; Matthias; Mller; Ladislav; Pina; Libor; Juha; Jorge; J.Rocca; Akira; Endo; Tomas; Mocek

    2014-01-01

    A preliminary investigation on short-wavelength ablation mechanisms of poly(methyl methacrylate)(PMMA) and poly(1,4-phenylene ether ether-sulfone)(PPEES) by extreme ultraviolet(EUV) radiation at 13.5 nm using a table-top laserproduced plasma from a gas-puff target at LLG(Gttingen) and at 46.9 nm by a 10 Hz desktop capillary discharge laser operated at the Institute of Physics(Prague) is presented.Ablation of polymer materials is initiated by photoinduced polymer chain scissions.The ablation occurs due to the formation of volatile products by the EUV radiolysis removed as an ablation plume from the irradiated material into the vacuum.In general,cross-linking of polymer molecules can compete with the chain decomposition.Both processes may influence the efficiency and quality of micro(nano)structuring in polymer materials.Wavelength is a critical parameter to be taken into account when an EUV ablation process occurs,because different wavelengths result in different energy densities in the near-surface region of the polymer exposed to nanosecond pulses of intense EUV radiation.

  2. The impact of hyperbaric oxygen therapy on serological values of vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF

    Ziebura Thomas

    2010-12-01

    Full Text Available Abstract Background Hyperbaric oxygen (HBO therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF and vascular endothelial growth factor (VEGF; their in-vivo function is still not fully understood. Methods Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO. Results There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature. Conclusions A significant effect of HBO on serum

  3. Lesion size in relation to ablation site during radiofrequency ablation

    Petersen, H H; Chen, X; Pietersen, A;

    1998-01-01

    performed during two different flow-velocities in a tissue bath, while electrode contact pressure and position were unchanged. Target temperature was 80 degrees C. Obtained tip temperature, power consumption and lesion dimensions were measured. In vivo lesion volume, depth and width were found significantly...... convective cooling by induction of a flow around the electrode tip increases lesion dimensions and power consumptions. Furthermore we conclude that for the given target temperature the power consumption is positively correlated with lesion volume (p <0.001), whereas the obtained tip temperature is not.......This study was designed to investigate the effect of the convective cooling of the tip of the ablation electrode during temperature controlled radiofrequency ablation. In vivo two different application sites in the left ventricle of anaesthetised pigs were ablated and in vitro ablation was...

  4. VEGF Levels in Plasma in Relation to Platelet Activation, Glycemic Control, and Microvascular Complications in Type 1 Diabetes

    Schlingemann, Reinier O.; van Noorden, Cornelis J. F.; Diekman, Mattheus J.M.; Tiller, Anna; Meijers, Joost C.M.; Koolwijk, Pieter; Wiersinga, Wilmar M.

    2013-01-01

    OBJECTIVE Increased levels of vascular endothelial growth factor (VEGF) in human plasma samples have suggested that circulating VEGF is a cause of endothelial dysfunction in diabetes mellitus. However, artificial release of VEGF from platelets as a source of VEGF in plasma samples, as also occurs in serum samples, has not been ruled out in these studies. RESEARCH DESIGN AND METHODS We determined VEGF levels in plasma collected in both citrate and PECT, a medium that inactivates platelets, in ...

  5. Anti-VEGF Therapy and the Retina: An Update

    Vikas Tah

    2015-01-01

    Full Text Available Ocular angiogenesis and macular oedema are major causes of sight loss across the world. Aberrant neovascularisation, which may arise secondary to numerous disease processes, can result in reduced vision as a result of oedema, haemorrhage, and scarring. The development of antivascular endothelial growth factor (anti-VEGF agents has revolutionised the treatment of retinal vasogenic conditions. These drugs are now commonly employed for the treatment of a plethora of ocular pathologies including choroidal neovascularisation, diabetic macular oedema, and retinal vein occlusion to name a few. In this paper, we will explore the current use of anti-VEGF in a variety of retinal diseases and the impact that these medications have had on visual outcome for patients.

  6. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium

    Fan, Xiujun; Krieg, Sacha; Kuo, Calvin J.; Wiegand, Stanley J; Rabinovitch, Marlene; Druzin, Maurice L.; Brenner, Robert M.; Giudice, Linda C.; Nayak, Nihar R.

    2008-01-01

    Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that ...

  7. Intravitreal anti-VEGF therapy in retinopathy of prematurity

    GÜNAY, Murat; ÇELİK, Gökhan

    2015-01-01

    Retinopathy of prematurity (ROP) is the retinal vascular developmental disorder of the premature infants and it is a leading cause of childhood blindness. Hypoxia secondary to the immature retina with subsequent release of some mediators establish the characteristic feature of ‘progressive retinopathy’. The most promoter one among these mediators is vascular endothelial growth factor (VEGF). The screening and treatment criteria were identified in past literature and successful treatment resul...

  8. Anti-VEGF for the Management of Diabetic Macular Edema

    Francisco Rosa Stefanini; Emmerson Badaró; Paulo Falabella; Michael Koss; Michel Eid Farah; Maurício Maia

    2014-01-01

    Diabetic retinopathy (DR) is an important cause of vision loss around the world, being the leading cause in the population between 20 and 60 years old. Among patients with DR, diabetic macular edema (DME) is the most frequent cause of vision impairment and represents a significant public health issue. Macular photocoagulation has been the standard treatment for this condition reducing the risk of moderate visual loss by approximately 50%. The role of vascular endothelial growth factor (VEGF) ...

  9. Corneal Neovascularization: An Anti-VEGF Therapy Review

    Chang, Jin-Hong; Garg, Nitin K.; Lunde, Elisa; Han, Kyu-Yeon; Jain, Sandeep; Azar, Dimitri T.

    2012-01-01

    Corneal neovascularization is a serious condition that can lead to a profound decline in vision. The abnormal vessels block light, cause corneal scarring, compromise visual acuity, and may lead to inflammation and edema. Corneal neovascularization occurs when the balance between angiogenic and antiangiogenic factors is tipped toward angiogenic molecules. Vascular endothelial growth factor (VEGF), one of the most important mediators of angiogenesis, is upregulated during neovascularization. In...

  10. Metronomic chemotherapy in metastatic breast cancer Impact on VEGF

    Background: Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents; including cyclophosphamide (CTX) and capecitabine (Cap) when given at lower doses for prolonged period (metronomic chemotherapy) postulating an antiangiogenic activity as well, Aim of work :To evaluate the action and tolerability of metronomic chemotherapy (MC) and its impact on serum vascular endothetial growth factor (VEGF) levels in metastatic breast cancer (MBC) patients. Patients and methods: In this study we evaluated the clinical efficacy and tolerability of low dose, capecitabine (500 mg twice daily) together with oral cyclophosphamide (CTX) (a dose of 50 mg once daily) in patients with metastatic breast cancer. Vascular endothelial growth factor (VEGF), an angiogenic marker, was measured in the serum samples; at base line, and after 2 and 6 months of therapy. Results: Sixty patients were evaluable. One achieved complete response (CR), 12 partial responses (PR), and 21 stable diseases (SD), while 26 were with progressive disease (PD). The overall response rate was 21.7% with overall disease control (CR, PR, and SD) 56.7%. The median time to progression was 7±2.59 months and overall survival 16 ±8.02 months. Toxicity was mild, Palmar-plantar erythrodythesia was the must common side effect and was observed in 22 patients (37%), leucopenia (Gl + 2) was the most common hematological toxicity, and it was reported in 27% of the cases. The median VEGF level was significantly declined after 2 and 6 months of therapy compared to the base line among the patients with disease control (CR, PR, and SD). In multivariate logisatic regression analysis, patients with post-menopausal, positive hormonal receptors, negative HER-2/Neu, and one, metastatic site, were statistically significant and have a better disease control rate. Coclcusions: MC induced drop in VEGF, and was

  11. Ion acceleration enhanced by target ablation

    Laser proton acceleration can be enhanced by using target ablation, due to the energetic electrons generated in the ablation preplasma. When the ablation pulse matches main pulse, the enhancement gets optimized because the electrons' energy density is highest. A scaling law between the ablation pulse and main pulse is confirmed by the simulation, showing that for given CPA pulse and target, proton energy improvement can be achieved several times by adjusting the target ablation

  12. MR靶向对比剂前体——VEGF165-适配体与VEGF165体外结合实验研究

    尤晓光; 白玉杰; 涂蓉

    2011-01-01

    目的应用酶联免疫吸附实验(ELISA)检测MR靶向对比剂前体——血管内皮生长因子165-适配体(VEGF165-aptamer)与VEGF165的体外结合能力,以了解其对VEGF的靶向性。方法实验组采用亲和素96孔酶标板,包被生物素化VEGF165-aptamer,设置递减的浓度梯度(共9组)和空白对照组,采用组间方差分析。结果实验组包被生物素化VEGF165-aptamer浓度在50~0.78pmol/μL时,实验组与空白组及实验各相邻组间差异有统计学意义(P0.05)。结论采用ELISA检测技术验证了VEGF165-aptamer与VEGF165间的体外结合能力,其有效最低小包被浓度为0.78pmol/μL,VEGF165-aptamer对VEGF165有良好的靶向性。

  13. Vaccination with a mutated variant of human Vascular Endothelial Growth Factor (VEGF) blocks VEGF-induced retinal neovascularization in a rabbit experimental model.

    Morera, Yanelys; González, Rafael; Lamdan, Humberto; Pérez, Lincidio; González, Yorlandis; Agüero, Judith; Castro, Jorge; Romero, Juan C; Etchegoyen, Ana Yansy; Ayala, Marta; Gavilondo, Jorge V

    2014-05-01

    Vascular Endothelial Growth Factor (VEGF) is a key driver of the neovascularization and vascular permeability that leads to the loss of visual acuity of eye diseases like wet age-related macular degeneration, diabetic macular edema, and retinopathy of premature. Among the several anti-VEGF therapies under investigation for the treatment of neovascular eye diseases, our group has developed the vaccine candidate CIGB-247-V that uses a mutated form of human VEGF as antigen. In this work we evaluated if the vaccine could prevent or attenuate VEGF-induced retinal neovascularization in the course of a rabbit eye neovascularization model, based on direct intravitreal injection of human VEGF. Our experimental findings have shown that anti-VEGF IgG antibodies induced by the vaccine were available in the retina blood circulation, and could neutralize in situ the neovascularization effect of VEGF. CIGB-247-V vaccination proved to effectively reduce retinal neovascularization caused by intravitreal VEGF injection. Altogether, these results open the way for human studies of the vaccine in neovascular eye syndromes, and inform on the potential mechanisms involved in its effect. PMID:24675387

  14. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

    Li Jing

    2011-06-01

    Full Text Available Abstract Background HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. Methods HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. Results Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P (P > 0.05. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P (P = 0.146. No correlation between HER-2/neu and VEGF expression was detected (P = 0.151. Conclusions HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.

  15. VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis

    Huang, Delong; Zhao, Chen; Ju, Rong; Kumar, Anil; Tian, Geng; Huang, Lijuan; Zheng, Lei; Li, Xianglin; Liu, Lixian; Wang, Shasha; Ren, Xiangrong; Ye, Zhimin; Chen, Wei; Xing, Liying; Chen, Qishan; Gao, Zhiqin; Mi, Jia; Tang, Zhongshu; Wang, Bin; Zhang, Shuping; Lee, Chunsik; Li, Xuri

    2016-01-01

    Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago. However, its role in hyperglycemia- and VEGF-A inhibition-induced retinal apoptosis remains unknown thus far. Yet, drugs that can block VEGF-B are being used to treat patients with diabetic retinopathy and other ocular neovascular diseases. It is therefore urgent to have a better understanding of the function of VEGF-B in these pathologies. Here, we report that both streptozotocin (STZ)-induced diabetes in rats and Macugen intravitreal injection in mice leads to retinal apoptosis in retinal ganglion cell and outer nuclear layers respectively. Importantly, VEGF-B treatment by intravitreal injection markedly reduced retinal apoptosis in both models. We further reveal that VEGF-B and its receptors, vascular endothelial growth factor 1 (VEGFR1) and neuropilin 1 (NP1), are abundantly expressed in rat retinae and choroids and are upregulated by high glucose with concomitant activation of Akt and Erk. These data highlight an important function of VEGF-B in protecting retinal cells from apoptosis induced by hyperglycemia and VEGF-A inhibition. VEGF-B may therefore have a therapeutic potential in treating various retinal degenerative diseases, and modulation of VEGF-B activity in the eye needs careful consideration. PMID:27189805

  16. VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis.

    Huang, Delong; Zhao, Chen; Ju, Rong; Kumar, Anil; Tian, Geng; Huang, Lijuan; Zheng, Lei; Li, Xianglin; Liu, Lixian; Wang, Shasha; Ren, Xiangrong; Ye, Zhimin; Chen, Wei; Xing, Liying; Chen, Qishan; Gao, Zhiqin; Mi, Jia; Tang, Zhongshu; Wang, Bin; Zhang, Shuping; Lee, Chunsik; Li, Xuri

    2016-01-01

    Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago. However, its role in hyperglycemia- and VEGF-A inhibition-induced retinal apoptosis remains unknown thus far. Yet, drugs that can block VEGF-B are being used to treat patients with diabetic retinopathy and other ocular neovascular diseases. It is therefore urgent to have a better understanding of the function of VEGF-B in these pathologies. Here, we report that both streptozotocin (STZ)-induced diabetes in rats and Macugen intravitreal injection in mice leads to retinal apoptosis in retinal ganglion cell and outer nuclear layers respectively. Importantly, VEGF-B treatment by intravitreal injection markedly reduced retinal apoptosis in both models. We further reveal that VEGF-B and its receptors, vascular endothelial growth factor 1 (VEGFR1) and neuropilin 1 (NP1), are abundantly expressed in rat retinae and choroids and are upregulated by high glucose with concomitant activation of Akt and Erk. These data highlight an important function of VEGF-B in protecting retinal cells from apoptosis induced by hyperglycemia and VEGF-A inhibition. VEGF-B may therefore have a therapeutic potential in treating various retinal degenerative diseases, and modulation of VEGF-B activity in the eye needs careful consideration. PMID:27189805

  17. COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

    Timoshenko, A V; Chakraborty, C; Wagner, G F; Lala, P K

    2006-01-01

    Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE2. Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors. PMID:16570043

  18. Field enhancement induced laser ablation

    Fiutowski, Jacek; Maibohm, Christian; Kjelstrup-Hansen, Jakob;

    Sub-diffraction spatially resolved, quantitative mapping of strongly localized field intensity enhancement on gold nanostructures via laser ablation of polymer thin films is reported. Illumination using a femtosecond laser scanning microscope excites surface plasmons in the nanostructures...

  19. Laser ablation in analytical chemistry.

    Russo, Richard E; Mao, Xianglei; Gonzalez, Jhanis J; Zorba, Vassilia; Yoo, Jong

    2013-07-01

    In 2002, we wrote an Analytical Chemistry feature article describing the Physics of Laser Ablation in Microchemical Analysis. In line with the theme of the 2002 article, this manuscript discusses current issues in fundamental research, applications based on detecting photons at the ablation site (LIBS and LAMIS) and by collecting particles for excitation in a secondary source (ICP), and directions for the technology. PMID:23614661

  20. Ablative therapy for liver tumours

    Dick, E A; Taylor-Robinson, S D; Thomas, H C; Gedroyc, W M W

    2002-01-01

    Established ablative therapies for the treatment of primary and secondary liver tumours, including percutaneous ethanol injection, cryotherapy, and radiofrequency ablation, are discussed. Newer techniques such as magnetic resonance imaging guided laser interstitial thermal therapy of liver tumours has produced a median survival rate of 40.8 months after treatment. The merits of this newly emerging technique are discussed, together with future developments, such as focused ultrasound therapy, ...

  1. Percutaneous Ablation of Hepatic Tumors

    McCarley, James R.; Soulen, Michael C.

    2010-01-01

    The liver is a common site of both primary and secondary malignancy resulting in significant morbidity and mortality. Careful patient evaluation and triage allows for optimal utilization of all oncologic therapies, including radiation, systemic chemotherapy, surgery, transarterial therapies, and ablation. Although the role of interventional oncologists in the management of hepatic malignancies continues to evolve, the use of percutaneous ablation therapies has proven to be an effective and mi...

  2. Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression

    Junichi Takino; Shoichi Yamagishi; Masayoshi Takeuchi

    2012-01-01

    AIM:To investigate the effect of glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs)on hepatocellular carcinoma (HCC) cells.METHODS:Two HCC cell lines (Hep3B and HepG2cells) and human umbilical vein endothelial cells (HUVEC) were used.Cell viability was determined using the WST-8 assay.Western blotting,enzyme linked immunosorbent assay,and real-time reverse transcriptionpolymerase chain reactions were used to detect protein and mRNA.Angiogenesis was evaluated by assessing the proliferation,migration,and tube formation of HUVEC.RESULTS:The receptor for AGEs (RAGE) protein was detected in Hep3B and HepG2 cells.HepG2 cells were not affected by the addition of Glycer-AGEs.GlycerAGEs markedly increased vascular endothelial growth factor (VEGF) mRNA and protein expression,which is one of the most potent angiogenic factors.Compared with the control unglycated bovine serum albumin (BSA)treatment,VEGF mRNA expression levels induced by the Glycer-AGEs treatment were 1.00 ± 0.10 vs 1.92± 0.09 (P < 0.01).Similarly,protein expression levels induced by the Glycer-AGEs treatment were 1.63 ± 0.04ng/mL vs 2.28 ± 0.17 ng/mL for the 24 h treatment and 3.36 ± 0.10 ng/mL vs 4.79 ± 0.31 ng/mL for the 48 h treatment,respectively (P < 0.01).Furthermore,compared with the effect of the control unglycated BSA-treated conditioned medium,the Glycer-AGEstreated conditioned medium significantly increased the proliferation,migration,and tube formation of HUVEC,with values of 122.4% ± 9.0% vs 144.5% ± 11.3% for cell viability,4.29 ± 1.53 vs 6.78 ± 1.84 for migration indices,and 71.0 ± 7.5 vs 112.4 ± 8.0 for the number of branching points,respectively (P < 0.01).CONCLUSION:These results suggest that Glycer-AGEs-RAGE signaling enhances the angiogenic potential of HCC cells by upregulating VEGF expression.

  3. Method development to quantify Bv8 expression in circulating CD11b+ cells in patients with neovascular age-related macular degeneration (nvAMD) exhibiting Anti-VEGF refractoriness.

    Catchpole, Timothy; Daniels, Tad; Perkins, Jill; Csaky, Karl G

    2016-07-01

    A subset of neovascular age-related macular degeneration (nvAMD) subjects appears to be refractory to the effects of anti-VEGF treatment and require frequent intravitreal injections. Prokineticin-2 (Bv8) expression in CD11b(+) cells has been linked to anti-VEGF response. We have developed a reproducible method to quantify gene expression in circulating CD11b + cells. Utilizing this method we tested the hypothesis that high Bv8 expression in circulating CD11b(+) cells is associated with anti-VEGF refractoriness in nvAMD patients. Two groups of nvAMD subjects undergoing treatment with anti-VEGF agents were recruited and classified as refractory or non-refractory to anti-VEGF treatment (n = 33 for each group). Two blood draws were obtained from each subject 1-9 months apart. Peripheral blood mononuclear cells (PBMCs) were isolated and CD11b(+) cells were purified via magnetic bead separation. RNA was purified, and relative expression of Bv8 among the subjects was compared via quantitative PCR analysis. Utilizing this approach no significant difference was detected in the mean LogRQ values between the first and second blood draws (t-test, p = 0.826) indicating low intra-patient variability and demonstrating good reproducibility of the assay. There was no significant difference in Bv8 expression between nvAMD subjects classified as refractory versus non-refractory. We were unable to find a correlation between Bv8 expression in CD11b + cells and anti-VEGF refractoriness in human nvAMD subjects. Relatively high expression in Bv8 in these subjects did not correlate with clinical treatment history, as measured by the frequency of injections. Utilizing this well characterized technique, studies are underway to examine alternative gene expression profiles in various circulating cell populations that may contribute to anti-VEGF refractoriness. PMID:27256991

  4. PGC-1alpha mediates exercise-induced skeletal muscle VEGF expression in mice

    Leick, Lotte; Hellsten, Ylva; Fentz, Joachim;

    2009-01-01

    littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1alpha KO mice, VEGF protein...... skeletal muscle VEGF protein expression approximately 50% in WT mice but with no effect in PGC-1alpha KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1alpha KO muscles. In addition, repeated AICAR treatments...... increased skeletal muscle VEGF protein expression approximately 15% in WT but not in PGC-1alpha KO mice. This study shows that PGC-1alpha is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein...

  5. Galectin-3 in patients undergoing ablation of atrial fibrillation

    Nicolas Clementy; Eric Piver; Nazih Benhenda; Anne Bernard; Bertrand Pierre; Edouard Siméon; Laurent Fauchier; Jean-Christophe Pagès; Dominique Babuty

    2014-01-01

    Background: Mechanisms of maintenance of atrial fibrillation are known to include fibrosis. Galectin-3, as a biomarker of fibrosis, may be a valuable marker of atrial remodeling. We sought to find whether there was a link between clinical features and higher galectin-3 levels in patients with atrial fibrillation. Methods: Serum concentrations of Galectin-3 were determined in a consecutive series of patients addressed for ablation of atrial fibrillation. Results: One-hundred-and-eighty-s...

  6. Enhancement of musculocutaneous nerve reinnervation after vascular endothelial growth factor (VEGF) gene therapy

    Haninec Pavel; Kaiser Radek; Bobek Vladimír; Dubový Petr

    2012-01-01

    Abstract Background Vascular endothelial growth factor (VEGF) is not only a potent angiogenic factor but it also promotes axonal outgrowth and proliferation of Schwann cells. The aim of the present study was to quantitatively assess reinnervation of musculocutaneous nerve (MCN) stumps using motor and primary sensory neurons after plasmid phVEGF transfection and end-to-end (ETE) or end-to-side (ETS) neurorrhaphy. The distal stump of rat transected MCN, was transfected with plasmid phVEGF, plas...

  7. Delivery of VEGF using Collagen-coated Polycaprolactone Scaffolds Stimulate Angiogenesis

    Singh, Shivani; Wu, Benjamin M.; Dunn, James C.Y.

    2011-01-01

    Establishing sufficient vascularization in scaffold remains a challenge for tissue-engineering. To improve angiogenesis, we incorporated vascular endothelial growth factor (VEGF) in collagen-coating over the porous polycaprolactone (PCL) scaffolds. The release kinetics of loaded VEGF from collagen-coated PCL (col-PCL) scaffolds was same as from scaffolds without the collagen. The bioactivity of VEGF delivered by the col-PCL scaffolds was confirmed by human umbilical vein endothelial cell (HUV...

  8. Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues

    Honek, J.; Seki, T.; Iwamoto, H; Fischer, C.; Li, J.; Lim, S.; Samani, N. J.; Zang, J; Cao, Y.

    2014-01-01

    The etiology and mechanisms underlying the age-related high incidence of metabolic diseases such as type 2 diabetes are not fully understood. In this paper, we show that blood vasculatures in the adipose tissues experience continuous changes during aging and VEGF is a key angiogenic factor controlling microvessel numbers and functions. Surprisingly, targeting VEGF and VEGF receptor 2 by specific blocking drugs produces different and sometimes opposing effects on white adipocytes, resulting in...

  9. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico); Gonzalez Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico)

    2010-10-15

    Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals

  10. Platelet Activation Determines Angiopoietin-1 and VEGF Levels in Malaria: Implications for Their Use as Biomarkers

    Judith Brouwers; Rintis Noviyanti; Rob Fijnheer; de Groot, Philip G.; Leily Trianty; Siti Mudaliana; Mark Roest; Din Syafruddin; Andre van der Ven; Quirijn de Mast

    2013-01-01

    INTRODUCTION: The angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity. Since platelets store large amounts of Ang-1 and VEGF, measurement of circulation levels of these proteins is sensitive to platelet number, in vivo platelet activation and inadvertent platelet activation during blood processing. We studied plasma Ang-1, Ang-2 and VEGF levels in malaria patients, taking the necessary precautio...

  11. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    Research highlights: → Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. → CoCl2-induced VEGF secretion in mast cells occurs by a Ca2+-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. → Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits FcεRI-dependent anaphylactic degranulation in mast cells. → Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl2) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl2 promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl2-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl2-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl2 in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent Fyn kinase activation.

  12. Vascular Endothelial Growth Factor (VEGF) in Seizures: A Double-Edged Sword

    Croll, Susan D.; Goodman, Jeffrey H.; Scharfman, Helen E.

    2004-01-01

    Vascular endothelial growth factor (VEGF) is a vascular growth factor which induces the development of new blood vessels (angiogenesis), vascular permeability, and inflammation. In brain, receptors for VEGF have been localized to vascular endothelium, neurons, and glia. VEGF is upregulated after hypoxic injury to the brain, such as occurs with cerebral ischemia or high-altitude edema, and has been implicated in the blood-brain barrier breakdown which occurs during these conditions. Given its ...

  13. Esophageal papilloma: Flexible endoscopic ablation byradiofrequency

    Gianmattia del Genio; Federica del Genio; Pietro Schettino; Paolo Limongelli; Salvatore Tolone; Luigi Brusciano; Manuela Avellino; Chiara Vitiello; Giovanni Docimo; Angelo Pezzullo; Ludovico Docimo

    2015-01-01

    Squamous papilloma of the esophagus is a rare benignlesion of the esophagus. Radiofrequency ablation is anestablished endoscopic technique for the eradication ofBarrett esophagus. No cases of endoscopic ablation ofesophageal papilloma by radiofrequency ablation (RFA)have been reported. We report a case of esophagealpapilloma successfully treated with a single sessionof radiofrequency ablation. Endoscopic ablation ofthe lesion was achieved by radiofrequency using anew catheter inserted through the working channelof endoscope. The esophageal ablated tissue wasremoved by a specifically designed cup. Completeablation was confirmed at 3 mo by endoscopy withbiopsies. This case supports feasibility and safety of asa new potential indication for BarrxTM RFA in patientswith esophageal papilloma.

  14. Effect of antisence VEGF on the radiosensitivity of esophageal cancer cells in vitro

    Objective: To investigate the effect of' antisense VEGF on the cell proliferation, VEGF protein expression and radiosensitivity of esophageal cancer cells in vitro. Methods: Fragments of antisense cDNA, empty vector plasmid DNA and antisense oligodeoxynucleotide of VEGF were transfected into esophageal cancer (TE-1) cells mediated with lipofectamine, respectively. Cell proliferating rate and apoptotic rate of these groups were edetected by MIT and FCM methods, respectively. After irradiation, the expression of VEGF in transfected cells were detected by using RT-PCR and Western blotting. The radiosensitivity of transfected cells were analyzed with colony forming assay. Results: After antisense cDNA plasmid and antisense oligodeoxynucleotide of VEGF were transfected successfully into TE-1 cells, expressions of VEGF protein decreased, however, the changes in cell growth rate and distribution of cell cycle, and the apoptotic rate were not observed in these transfected cells. After irradiation, the radiosensitivity of transfected TE-1 cells were increased, but there was no significant difference in cell growth rate among groups. The apoptotic rates in antisense groups increased slightly compared to TE-1 and TE-1-E groups. Conclusions: Expression of VEGF mRNA and VEGF protein were significantly suppressed in TE-1 cells transfected by antisense cDNA and antisense oligodeoxynucleotide of VEGF. After irradiation, the radiosensitivity of the transfected TE-1 cells was increased. (authors)

  15. Transgenic overexpression of VEGF-C induces weight gain and insulin resistance in mice

    Karaman, Sinem; Hollmén, Maija; Yoon, Sun-Young; Alkan, H. Furkan; Alitalo, Kari; Wolfrum, Christian; Detmar, Michael

    2016-01-01

    Obesity comprises great risks for human health, contributing to the development of other diseases such as metabolic syndrome, type 2 diabetes and cardiovascular disease. Previously, obese patients were found to have elevated serum levels of VEGF-C, which correlated with worsening of lipid parameters. We recently identified that neutralization of VEGF-C and -D in the subcutaneous adipose tissue during the development of obesity improves metabolic parameters and insulin sensitivity in mice. To test the hypothesis that VEGF-C plays a role in the promotion of the metabolic disease, we used K14-VEGF-C mice that overexpress human VEGF-C under control of the keratin-14 promoter in the skin and monitored metabolic parameters over time. K14-VEGF-C mice had high levels of VEGF-C in the subcutaneous adipose tissue and gained more weight than wildtype littermates, became insulin resistant and had increased ectopic lipid accumulation at 20 weeks of age on regular mouse chow. The metabolic differences persisted under high-fat diet induced obesity. These results indicate that elevated VEGF-C levels contribute to metabolic deterioration and the development of insulin resistance, and that blockade of VEGF-C in obesity represents a suitable approach to alleviate the development of insulin resistance. PMID:27511834

  16. A Biomimic Reconstituted High Density Lipoprotein Nanosystem for Enhanced VEGF Gene Therapy of Myocardial Ischemia

    Xiaotian Sun

    2015-01-01

    Full Text Available A biomimic reconstituted high density lipoprotein (rHDL based system, rHDL/Stearic-PEI/VEGF complexes, was fabricated as an advanced nanovector for delivering VEGF plasmid. Here, Stearic-PEI was utilized to effectively condense VEGF plasmid and to incorporate the plasmid into rHDL. The rHDL/Stearic-PEI/VEGF complexes with diameter under 100 nm and neutral surface charge demonstrated enhanced stability under the presence of bovine serum albumin. Moreover, in vitro cytotoxicity and transfection assays on H9C2 cells further revealed their superiority, as they displayed lower cytotoxicity with much higher transfection efficiency when compared to PEI 10K/VEGF and Lipos/Stearic-PEI/VEGF complexes. In addition, in vivo investigation on ischemia/reperfusion rat model implied that rHDL/Stearic-PEI/VEGF complexes possessed high transgene capacity and strong therapeutic activity. These findings indicated that rHDL/Stearic-PEI/VEGF complexes could be an ideal gene delivery system for enhanced VEGF gene therapy of myocardial ischemia, which might be a new promising strategy for effective myocardial ischemia treatment.

  17. Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor.

    Acevedo, Lisette M; Barillas, Samuel; Weis, Sara M; Göthert, Joachim R; Cheresh, David A

    2008-03-01

    Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF- but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGF- but not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a function-blocking Nrp-1 antibody. While both Sema3A- and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF- but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP. PMID:18180379

  18. Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction†

    Jarvis, Ashley; Allerston, Charles K.; Jia, Haiyan; Herzog, Birger; Garza-Garcia, Acely; Winfield, Natalie; Ellard, Katie; Aqil, Rehan; Lynch, Rosemary; Chapman, Chris; Hartzoulakis, Basil; Nally, James; Stewart, Mark; Cheng, Lili; Menon, Malini

    2010-01-01

    We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1−ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 an...

  19. Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced-sepsis through EPO-R, VEGF and VEGF-R2 modulation.

    Heitrich, Mauro; García, Daiana Maria de Los Ángeles; Stoyanoff, Tania Romina; Rodríguez, Juan Pablo; Todaro, Juan Santiago; Aguirre, María Victoria

    2016-08-01

    Sepsis remains the most important cause of acute kidney injury (AKI) and acute lung injury (ALI) in critically ill patients. The cecal ligation and puncture (CLP) model in experimental mice reproduces most of the clinical features of sepsis. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and pro-angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO protection through the expression of the EPO/EPO receptor (EPO-R) and VEGF/VEF-R2 systems in kidneys and lungs of mice undergoing CLP-induced sepsis. Male inbred Balb/c mice were divided in three experimental groups: Sham, CLP, and CLP+EPO (3000IU/kg sc). Assessment of renal functional parameters, survival, histological examination, immunohistochemistry and/or Western blottings of EPO-R, VEGF and VEGF-R2 were performed at 18h post-surgery. Mice demonstrated AKI by elevation of serum creatinine and renal histologic damage. EPO treatment attenuates renal dysfunction and ameliorates kidney histopathologic changes. Additionally, EPO administration attenuates deleterious septic damage in renal cortex through the overexpression of EPO-R in tubular interstitial cells and the overexpression of the pair VEGF/VEGF-R2. Similarly CLP- induced ALI, as evidenced by parenchymal lung histopathologic alterations, was ameliorated through pulmonary EPO-R, VEGF and VEGF-R2 over expression suggesting and improvement in endothelial survival and functionality. This study demonstrates that EPO exerts protective effects in kidneys and lungs in mice with CLP-induced sepsis through the expression of EPO-R and the regulation of the VEGF/VEGF-R2 pair. PMID:27470403

  20. Alteration of protein expression pattern of vascular endothelial growth factor (VEGF) from soluble to cell-associated isoform during tumourigenesis

    Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells, and its expression has been correlated with increased tumour angiogenesis. Although numerous publications dealing with the measurement of circulating VEGF for diagnostic and therapeutic monitoring have been published, the relationship between the production of tissue VEGF and its concentration in blood is still unclear. The aims of this study were to determine: 1) The expression pattern of VEGF isoforms at the protein level in colorectal and lung adenocarcinoma in comparison to the pattern in corresponding adjacent normal tissues 2) The relationship between the expression pattern of VEGF and total level of circulating VEGF in the blood to clarify whether the results of measuring circulating VEGF can be used to predict VEGF expression in tumour tissues. Ninety-four tissue samples were obtained from patients, 76 colorectal tumour tissues and 18 lung tumour tissues. VEGF protein expression pattern and total circulating VEGF were examined using western blot and capture ELISA, respectively. Three major protein bands were predominately detected in tumour samples with an apparent molecular mass under reducing conditions of 18, 23 and 26 kDa. The 18 kDa VEGF protein was expressed equally in both normal and colorectal tumour tissues and predominately expressed in normal tissues of lung, whereas the 23 and 26 kDa protein was only detected at higher levels in tumour tissues. The 18, 23 and 26 kDa proteins are believed to represent the VEGF121, the VEGF165 and the VEGF189, respectively. There was a significant correlation of the expression of VEGF165 with a smaller tumour size maximum diameter <5 cm (p < 0.05), and there was a significant correlation of VEGF189 with advanced clinical stage of colorectal tumours. The measurement of total circulating VEGF in serum revealed that cancer patients significantly (p < 0.001) possessed a higher level of circulating VEGF (1081 ± 652 pg/ml in colorectal

  1. Local thermal ablation of renal cell carcinoma

    Purpose: With evolving local thermal ablation technology, the clinical application of thermal ablation has been actively investigated in the treatment for renal cell carcinoma. We review the evolution and current status of radiofrequency ablation and microwave ablation for renal cell carcinoma. Materials and methods: All articles published in English on radiofrequency ablation or microwave ablation as a treatment for renal cell carcinoma were identified with a MEDLINE® and PubMed® search from 1990 to 2010. Results: Local thermal ablation has several advantages, including keeping more normal renal units, relatively simple operation, easy tolerance, fewer complications, a shorter hospitalization and convalescence period. Long-term data has determined radiofrequency ablation is responsible for poor surgical candidates with renal cell carcinoma, however, tumor size, location and shape might affect the efficacy of radiofrequency ablation. Microwave ablation can induce large ablation volumes and yield good local tumor control. Associated complications appear to be low. Conclusions: Local ablative approaches seem to represent an attractive alternative to extirpative surgery for the treatment of small renal neoplasms in select patients. Potential developments include concepts to improve the accuracy and effectiveness of thermal ablation by improving the guiding, monitoring capabilities and detection capacity of multi-center lesions to provide at least equivalent cancer control to conventional surgery.

  2. In vivo characterization of {sup 68}Ga-NOTA-VEGF{sub 121} for the imaging of VEGF receptor expression in U87MG tumor xenograft models

    Kang, Choong Mo; Koo, Hyun-Jung; Lee, Kyung-Han; Choe, Yearn Seong [Sungkyunkwan University School of Medicine, Department of Nuclear Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Sung-Min; Yim, Min Su; Ryu, Eun Kyoung [Korea Basic Science Institute, Division of Magnetic Resonance Research, Chungbuk (Korea, Republic of)

    2013-02-15

    Vascular endothelial growth factor receptors (VEGFRs) are associated with tumor growth and induction of tumor angiogenesis and are known to be overexpressed in various human tumors. In the present study, we prepared and evaluated {sup 68}Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid-benzyl (NOTA)-VEGF{sub 121} as a positron emission tomography (PET) radioligand for the in vivo imaging of VEGFR expression. {sup 68}Ga-NOTA-VEGF{sub 121} was prepared by conjugation of VEGF{sub 121} and p-SCN-NOTA, followed by radiolabeling with {sup 68}GaCl{sub 3} and then purification using a PD-10 column. Human aortic endothelial cell (HAEC) binding of {sup 68}Ga-NOTA-VEGF{sub 121} was measured as a function of time. MicroPET and biodistribution studies of U87MG tumor xenografted mice were performed at 1, 2, and 4 h after injection of {sup 68}Ga-NOTA-VEGF{sub 121}. The tumor tissues were then sectioned and subjected to immunostaining. The decay-corrected radiochemical yield of {sup 68}Ga-NOTA-VEGF{sub 121} was 40 {+-} 4.5 % and specific activity was 243.1 {+-} 104.6 GBq/{mu}mol (8.6 {+-} 3.7 GBq/mg). {sup 68}Ga-NOTA-VEGF{sub 121} was avidly taken up by HAECs in a time-dependent manner, and the uptake was blocked either by 32 % with VEGF{sub 121} or by 49 % with VEGFR2 antibody at 4 h post-incubation. In microPET images of U87MG tumor xenografted mice, radioactivity was accumulated in tumors (2.73{+-}0.32 %ID/g at 2 h), and the uptake was blocked by 40 % in the presence of VEGF{sub 121}. In biodistribution studies, tumor uptake (1.84{+-}0.14 %ID/g at 2 h) was blocked with VEGF{sub 121} at a similar level (52 %) to that of microPET images. Immunostaining analysis of U87MG tumor tissues obtained after the microPET imaging showed high levels of VEGFR2 expression. These results demonstrate that {sup 68}Ga-NOTA-VEGF{sub 121} has potential for the in vivo imaging of VEGFR expression. In addition, our results also suggest that the in vivo characteristics of radiolabeled VEGF depend on the

  3. Corneal avascularity is due to soluble VEGF receptor-1.

    Ambati, Balamurali K; Nozaki, Miho; Singh, Nirbhai; Takeda, Atsunobu; Jani, Pooja D; Suthar, Tushar; Albuquerque, Romulo J C; Richter, Elizabeth; Sakurai, Eiji; Newcomb, Michael T; Kleinman, Mark E; Caldwell, Ruth B; Lin, Qing; Ogura, Yuichiro; Orecchia, Angela; Samuelson, Don A; Agnew, Dalen W; St Leger, Judy; Green, W Richard; Mahasreshti, Parameshwar J; Curiel, David T; Kwan, Donna; Marsh, Helene; Ikeda, Sakae; Leiper, Lucy J; Collinson, J Martin; Bogdanovich, Sasha; Khurana, Tejvir S; Shibuya, Masabumi; Baldwin, Megan E; Ferrara, Napoleone; Gerber, Hans-Peter; De Falco, Sandro; Witta, Jassir; Baffi, Judit Z; Raisler, Brian J; Ambati, Jayakrishna

    2006-10-26

    Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea. PMID:17051153

  4. Corneal avascularity is due to soluble VEGF receptor-1

    Ambati, Balamurali K.; Nozaki, Miho; Singh, Nirbhai; Takeda, Atsunobu; Jani, Pooja D.; Suthar, Tushar; Albuquerque, Romulo J. C.; Richter, Elizabeth; Sakurai, Eiji; Newcomb, Michael T.; Kleinman, Mark E.; Caldwell, Ruth B.; Lin, Qing; OGURA, Yuichiro; Orecchia, Angela

    2006-01-01

    Corneal avascularity—the absence of blood vessels in the cornea—is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders1-4. But the molecular underpinnings of the avascular phenotype have until now remained obscure5-10 and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and th...

  5. Identification of an exonic splicing silencer in exon 6A of the human VEGF gene

    Crystal Ronald G

    2009-11-01

    Full Text Available Abstract Background The different isoforms of vascular endothelial growth factor (VEGF play diverse roles in vascular growth, structure and function. Alternative splicing of the VEGF gene results in the expression of three abundant isoforms: VEGF121, VEGF165 and VEGF189. The mRNA for VEGF189 contains the alternatively spliced exon 6A whereas the mRNA for VEGF165 lacks this exon. The objective of this study was to identify the cis elements that control utilization of exon 6A. A reporter minigene was constructed (pGFP-E6A containing the coding sequence for GFP whose translation was dependent on faithful splicing for removal of the VEGF exon 6A. To identify cis-acting splicing elements, sequential deletions were made across exon 6A in the pGFP-E6A plasmid. Results A candidate cis-acting exonic splicing silencer (ESS comprising nucleotides 22-30 of exon 6A sequence was identified corresponding to the a silencer consensus sequence of AAGGGG. The function of this sequence as an ESS was confirmed in vivo both in the context of the reporter minigene as a plasmid and in the context of a longer minigene with VEGF exon 6A in its native context in an adenoviral gene transfer vector. Further mutagenesis studies resulted in the identification of the second G residue of the putative ESS as the most critical for function. Conclusion This work establishes the identity of cis sequences that regulate alternative VEGF splicing and dictate the relative expression levels of VEGF isoforms.

  6. A two-compartment model of VEGF distribution in the mouse.

    Phillip Yen

    Full Text Available Vascular endothelial growth factor (VEGF is a key regulator of angiogenesis--the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model. The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF(120 and VEGF(164 and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in

  7. Surgical Ablation of Atrial Fibrillation.

    Ramlawi, Basel; Abu Saleh, Walid K

    2015-01-01

    The Cox-maze procedure for the restoration of normal sinus rhythm, initially developed by Dr. James Cox, underwent several iterations over the years. The main concept consists of creating a series of transmural lesions in the right and left atria that disrupt re-entrant circuits responsible for propagating the abnormal atrial fibrillation rhythm. The left atrial appendage is excluded as a component of the Maze procedure. For the first three iterations of the Cox- maze procedure, these lesions were performed using a surgical cut-and-sew approach that ensured transmurality. The Cox-Maze IV is the most currently accepted iteration. It achieves the same lesion set of the Cox- maze III but uses alternative energy sources to create the transmural lesions, potentially in a minimally invasive approach on the beating heart. High-frequency ultrasound, microwave, and laser energy have all been used with varying success in the past. Today, bipolar radiofrequency heat or cryotherapy cooling are the most accepted sources for creating linear lesions with consistent safety and transmurality. The robust and reliable nature of these energy delivery methods has yielded a success rate reaching 90% freedom from atrial fibrillation at 12 months. Such approaches offer a significant long-term advantage over catheter-based ablation, especially in patients having longstanding, persistent atrial fibrillation with characteristics such as dilated left atrial dimensions, poor ejection fraction, and failed catheter ablation. Based on these improved results, there currently is significant interest in developing a hybrid ablation strategy that incorporates the superior transmural robust lesions of surgical ablation, the reliable stroke prevention potential of epicardial left atrial appendage exclusion, and sophisticated mapping and confirmatory catheter-based ablation technology. Such a minimally invasive hybrid strategy for ablation may lead to the development of multidisciplinary "Afib teams" to

  8. Microwave ablation of hepatocellular carcinoma

    2015-01-01

    Although surgical resection is still the optimal treatmentoption for early-stage hepatocellular carcinoma(HCC) in patients with well compensated cirrhosis,thermal ablation techniques provide a valid nonsurgicaltreatment alternative, thanks to their minimalinvasiveness, excellent tolerability and safety profile,proven efficacy in local disease control, virtuallyunlimited repeatability and cost-effectiveness. Differentenergy sources are currently employed in clinics asphysical agents for percutaneous or intra-surgicalthermal ablation of HCC nodules. Among them, radiofrequency(RF) currents are the most used, whilemicrowave ablations (MWA) are becoming increasinglypopular. Starting from the 90s', RF ablation (RFA) rapidlybecame the standard of care in ablation, especially inthe treatment of small HCC nodules; however, RFAexhibits substantial performance limitations in thetreatment of large lesions and/or tumors located nearmajor heat sinks. MWA, first introduced in the FarEastern clinical practice in the 80s', showing promisingresults but also severe limitations in the controllabilityof the emitted field and in the high amount of poweremployed for the ablation of large tumors, resultingin a poor coagulative performance and a relativelyhigh complication rate, nowadays shows better resultsboth in terms of treatment controllability and of overallcoagulative performance, thanks to the improvementof technology. In this review we provide an extensiveand detailed overview of the key physical and technicalaspects of MWA and of the currently available systems,and we want to discuss the most relevant published dataon MWA treatments of HCC nodules in regard to clinicalresults and to the type and rate of complications, both inabsolute terms and in comparison with RFA.

  9. Microwave ablation of hepatocellular carcinoma.

    Poggi, Guido; Tosoratti, Nevio; Montagna, Benedetta; Picchi, Chiara

    2015-11-01

    Although surgical resection is still the optimal treatment option for early-stage hepatocellular carcinoma (HCC) in patients with well compensated cirrhosis, thermal ablation techniques provide a valid non-surgical treatment alternative, thanks to their minimal invasiveness, excellent tolerability and safety profile, proven efficacy in local disease control, virtually unlimited repeatability and cost-effectiveness. Different energy sources are currently employed in clinics as physical agents for percutaneous or intra-surgical thermal ablation of HCC nodules. Among them, radiofrequency (RF) currents are the most used, while microwave ablations (MWA) are becoming increasingly popular. Starting from the 90s', RF ablation (RFA) rapidly became the standard of care in ablation, especially in the treatment of small HCC nodules; however, RFA exhibits substantial performance limitations in the treatment of large lesions and/or tumors located near major heat sinks. MWA, first introduced in the Far Eastern clinical practice in the 80s', showing promising results but also severe limitations in the controllability of the emitted field and in the high amount of power employed for the ablation of large tumors, resulting in a poor coagulative performance and a relatively high complication rate, nowadays shows better results both in terms of treatment controllability and of overall coagulative performance, thanks to the improvement of technology. In this review we provide an extensive and detailed overview of the key physical and technical aspects of MWA and of the currently available systems, and we want to discuss the most relevant published data on MWA treatments of HCC nodules in regard to clinical results and to the type and rate of complications, both in absolute terms and in comparison with RFA. PMID:26557950

  10. Femtosecond laser ablation of dentin

    The surface morphology, structure and composition of human dentin treated with a femtosecond infrared laser (pulse duration 500 fs, wavelength 1030 nm, fluences ranging from 1 to 3 J cm-2) was studied by scanning electron microscopy, x-ray diffraction, x-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. The average dentin ablation threshold under these conditions was 0.6 ± 0.2 J cm-2 and the ablation rate achieved in the range 1 to 2 µm/pulse for an average fluence of 3 J cm-2. The ablation surfaces present an irregular and rugged appearance, with no significant traces of melting, deformation, cracking or carbonization. The smear layer was entirely removed by the laser treatment. For fluences only slightly higher than the ablation threshold the morphology of the laser-treated surfaces was very similar to the dentin fracture surfaces and the dentinal tubules remained open. For higher fluences, the surface was more porous and the dentin structure was partially concealed by ablation debris and a few resolidified droplets. Independently on the laser processing parameters and laser processing method used no sub-superficial cracking was observed. The dentin constitution and chemical composition was not significantly modified by the laser treatment in the processing parameter range used. In particular, the organic matter is not preferentially removed from the surface and no traces of high temperature phosphates, such as the β-tricalcium phosphate, were observed. The achieved results are compatible with an electrostatic ablation mechanism. In conclusion, the high beam quality and short pulse duration of the ultrafast laser used should allow the accurate preparation of cavities, with negligible damage of the underlying material. (paper)

  11. Transhemangioma Ablation of Hepatocellular Carcinoma

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  12. Transhemangioma Ablation of Hepatocellular Carcinoma

    Pua, Uei, E-mail: druei@yahoo.com [Tan Tock Seng Hospital, Department of Diagnostic Radiology (Singapore)

    2012-12-15

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  13. Soft thrombus formation in radiofrequency catheter ablation

    Demolin, JM; Eick, OJ; Munch, K; Koullick, E; Nakagawa, H; Wittkampf, FHM

    2002-01-01

    During RF catheter ablation, local temperature elevation can result in coagulum formation on the ablation electrode, resulting in impedance rise. A recent study has also demonstrated the formation of a so-called soft thrombus during experimental ablations. This deposit poorly adhered to the catheter

  14. Ablation of Solid Hydrogen in a Plasma

    Jørgensen, L. W.; Sillesen, Alfred Hegaard

    1979-01-01

    Several hydrogen pellet ablation models based on the formation of a shielding neutral cloud have been reported by different authors. The predicted ablation rates are shown to follow almost the same scaling law and this is used to explain the authors' ablation experiment....

  15. Laser ablation at the hydrodynamic regime

    Gojani Ardian B.

    2013-01-01

    Laser ablation of several metals and PVC polymer by high energy nanosecond laser pulses is investigated experimentaly. Visualization by shadowgraphy revealed the dynamics of the discontinuities in ambient air and ablation plume above the target surface, while surface profiling allowed for determination of the ablated mass.

  16. Anti-VEGF agents in metastatic colorectal cancer (mCRC: are they all alike?

    Saif MW

    2013-06-01

    Full Text Available Muhammad Wasif Saif GI Oncology Program, Tufts University School of Medicine, Boston, MA, USA Abstract: Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States, VEGF receptors (eg, ramucirumab, and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors. The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012, using search terms including, but not limited to: “bevacizumab,” “aflibercept,” “ramucirumab,” and “IMC-18F1.” Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking. Keywords: aflibercept, antiangiogenesis, metastatic colorectal cancer (mCRC, tyrosine kinase inhibitor (TKI, vascular endothelial growth factor (VEGF

  17. Contraction induced secretion of VEGF from skeletal muscle cells is mediated by adenosine

    Høier, Birgitte; Olsen, Karina; Nyberg, Michael Permin; Bangsbo, Jens; Hellsten, Ylva

    2010-01-01

    and during knee extensor exercise. The dialysate was analyzed for content of VEGF protein and adenosine. The mechanism of VEGF secretion from muscle cells in culture was examined in resting and electro stimulated cells, and in response to the adenosine analogue NECA, and the adenosine A(2A) receptor...

  18. Effect of VEGF, P53 and telomerase on angiogenesis of gastric carcinoma tissue

    Yan-Fang Yu; Yong Zhang; Na Shen; Rui-Ying Zhang; Xin-Qing Lu

    2014-01-01

    Objective: To investigate the effect of vascular endothelial growth factor (VEGF), P53 and telomerase on angiogenesis in gastric carcinoma tissue. Methods: A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF, P53 and telomerase expression using immunohistochemical methods. Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed. Results:Microvascular density (MVD) and the expression of VEGF, P53 and telomerase were positively correlated. Expression of VEGF and P53 protein were related to tumor type and lymph metastasis, and also a correlation was observed between P53 and VEGF. The telomerase expression had no correlation with VEGF, and P53. Conclusions: VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis. Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF. Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53.

  19. Correlation of VEGF and COX-2 Expression with VM in Malignant Melanomas

    BaocunSun; ShiwuZhang; XiulanZhao; YanxueLiu; ChunshengNi; DanfangZhang; HongQi; ZhiyongLiu; XishanHao

    2004-01-01

    OBJECTIVE To investigate the relationship between vascular epithelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in melanomas and the expressive difference of VEGF and COX-2 between melanomas with and without vasculogenic mimicry(VM).METHODS Sixty cases of malignant melanomas emoeaaea In paraffin were studied. The tumors were divided into a high-grade malignant group and a low-grade malignant group based on their tumor type, atypia and survival time of the patient. Then tissue microarrays were produced from these paraffin-embedded tumor tissues which were stained for VEGF, COX-2 and PAS. The difference in expression between VEGF and COX-2 in the malignant melanomas was compared using a grid-count. In addition, the tumors were also divided into mimicry and non-mimicry groups based on their PAS staining. Then the differences between the PAS positive and negative areas of the 2 groups were compared.RESULTS In malignant melanomas with VM, VEGF and COX-2 expression was less in tumors in which VM was absent, but VEGF, COX-2 expression in high-grade malignant melanomas was higher than that in low-grade grade malignant melanomas. Expression of VEGF was correlated with COX-2 expression.CONCLUSION VM exists in some high-grade malignant melanomas. The differences and relations between VEGF and COX-2 showed that some high-grade malignant melanomas possess a unique molecular-mechanism of tumor metastasis and blood supply.

  20. Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis.

    Morfoisse, Florent; Tatin, Florence; Hantelys, Fransky; Adoue, Aurelien; Helfer, Anne-Catherine; Cassant-Sourdy, Stephanie; Pujol, Françoise; Gomez-Brouchet, Anne; Ligat, Laetitia; Lopez, Frederic; Pyronnet, Stephane; Courty, Jose; Guillermet-Guibert, Julie; Marzi, Stefano; Schneider, Robert J; Prats, Anne-Catherine; Garmy-Susini, Barbara H

    2016-08-01

    The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5' UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5'UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394-405. ©2016 AACR. PMID:27280395

  1. Pulmonary Large Cell Carcinoma Displays High Expression of EMMPRIN and VEGF

    Yushuang Zheng; Miao Yu; Huachuan Zheng; Yifu Guan; Yasuo Takano

    2008-01-01

    OBJECTIVE To investigate the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and vascular endothelial growth factor (VEGF) in lung carcinomas,and to clarify their roles in carcinoma progression.METHODS Expression of EMMPRIN and VEGF was examined with tissue microarrays (TMAs) of lung carcinomas (n = 181),and their suppression in adjacent normal lung samples (n = 40) were determined by immunohistochemistry.The results were compared with clinicopathological findings for the same tumors.RESULTS Both EMMPRIN and VEGF were occasionally expressed in pseudostratified columnar epithelium and frequently in lung carcinomas.Histologically,EMMPRIN and VEGF displayed higher levels in large (LCC) cell carcinomas than adenocarcinoma (AD),squamous (SQ) and small cell carcinomas (SCC) (P < 0.05).EMMPRIN was more highly expressed in SQ as compared with AD (P < 0.05),while the converse was true for VEGF (P < 0.05).Binding was generally more intense for EMMPRIN in samples from male compared to female patients (P < 0.05),whereas the latter tended to exhibit more VEGF expression (P < 0.05).Positive associations of VEGF expression with the TNM stage and amounts of EMMPRIN were noted in the lung carcinomas (P < 0.05).CONCLUSION EMMPRIN and VEGF possibly contribute to physiological repair of normal lung and histogenesis of lung carcinoma.Both proteins might be involved in the molecular basis for differences in the incidence of lung carcinoma between men and women.

  2. RNA interference inhibits expression of vascular endothelial growth factor (VEGF) in human retinal pigment epithelial cells

    CAI Chun-mei; SUN Bao-chen; LIU Xu-yang; WANG Jin-jin; LI Jun-fa; HAN Song; WANG Ning-li; LU Qing-jun

    2005-01-01

    @@ Choroidal neovascularization (CNV), a major cause of vision loss, is the result of the increased vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial (RPE) cells. It is important to inhibit the expression of VEGF protein in RPE cells.

  3. Activation of Protease-Activated Receptor 2 Induces VEGF Independently of HIF-1

    Rasmussen, Jeppe Grøndahl; Riis, Simone Elkjær; Frøbert, Ole; Yang, Sufang; Kastrup, Jens; Zachar, Vladimir; Simonsen, Ulf; Fink, Trine

    2012-01-01

    Background Human adipose stem cells (hASCs) can promote angiogenesis through secretion of proangiogenic factors such as vascular endothelial growth factor (VEGF). In other cell types, it has been shown that induction of VEGF is mediated by both protease activated receptor 2 (PAR2) and hypoxia inducible factor 1(HIF-1). The present study hypothesized that PAR2 stimulation through activation of kinase signaling cascades lead to induction of HIF-1 and secretion of VEGF. Methodology/Principal Findings Immunohistochemistry revealed the expression of PAR2 receptors on the surface of hASCs. Blocking the PAR2 receptors with a specific antibody prior to trypsin treatment showed these receptors are involved in trypsin-evoked increase in VEGF secretion from hASCs. Blocking with specific kinase inhibitors suggested that that activation of MEK/ERK and PI3-kinase/Akt pathways are involved in trypsin-eveoked induction of VEGF. The effect of the trypsin treatment on the transcription of VEGF peaked at 6 hours after the treatment and was comparable to the activation observed after keeping hASCs for 24 hours at 1% oxygen. In contrast to hypoxia, trypsin alone failed to induce HIF-1 measured with ELISA, while the combination of trypsin and hypoxia had an additive effect on both VEGF transcription and secretion, results which were confirmed by Western blot. Conclusion In hASCs trypsin and hypoxia induce VEGF expression through separate pathways. PMID:23049945

  4. Expression profiling of ETS and MMP factors in VEGF-activated endothelial cells: role of MMP-10 in VEGF-induced angiogenesis.

    Heo, Sun-Hee; Choi, Young-Jin; Ryoo, Hyun-Mo; Cho, Je-Yoel

    2010-09-01

    In the process of angiogenesis, working of many transcription factors at the proper time is important to activate angiogenesis-related genes such as cytokine, matrix protease and adhesion molecules. In this study, we searched for Ets transcription factors and matrix metalloproteinases (MMPs) that respond to VEGF in endothelial cells. We first analyzed the expression of 27 human Ets factors and 15 human MMPs in VEGF-treated human umbilical vein endothelial cells (HUVEC) using quantitative RT-PCR. The most abundant Ets factors in HUVEC were ETS-1, Fli-1, ERP/NET/ELK3, and ERG. MMP-1, -2, -10, -11, -14, -15, and -16 were also detected in HUVEC. We also found that ETV-1, Fli-1, ERG, MMP-1, -3, -7, -8, -9, -10, -13, and -19 expression is up-regulated more than 1.5-fold in HUVEC after 2 h of VEGF treatment. In addition, the expression of MMP-10 induced by VEGF remained twofold higher for 24 h compared to non-treated control. The elevation of MMP10 mRNA and protein levels was confirmed to be both time- and dosage-dependent. In addition, MMP-10 transcription was mediated by Ets-1 but not ERP/NET/ELK3. The inhibition of PI3K and MAPK inhibited VEGF-induced MMP-10 expression. Furthermore, transfection of MMP-10 siRNA inhibited VEGF-induced migration and tube formation in HUVEC, and it also inhibited vessel formation in matrigel plugs in vivo. In conclusion, our study demonstrated induction of MMP-10 by VEGF in HUVEC and supports an angiogenic role for MMP-10 in response to VEGF stimulation in vitro and in vivo. PMID:20432469

  5. Expression and significance of VEGF and p53 in degenerate intervertebral disc tissue

    Xiao-Yu Lu; Xiao-Hong Ding; Li-Jun Zhong; Hong Xia; Xiao-Dong Chen; Hai Huang

    2013-01-01

    Objective: To investigate the mechanism of expression and significance of vascular endothelial growth factor (VEGF) and p53 in degenerate intervertebral disc tissue. Methods: Pathological sections collected from 156 patients with lumbar disc herniation after surgery were tested by immunohistochemistry method, for evaluation of the expression of VEGF and p53 in degenerate intervertebral disc tissue. Results: 98 cases (62.8%) with vascular infiltration phenomenon are found, and positive rates of VEGF and p53 in degenerate intervertebral disc tissue are 73.42%(116/156) and 58.97% (92/156); co-expression rate is 53.2%(83/156); the expression rates of VEFG and p53 are significantly higher in the tissue with blood vessel infiltration than in the tissue without infiltration; there is a close relationship of VEGF with p53. Conclusions: VEGF and p53 gene synergetic express in degenerate intervertebral disc tissue, working together in neovascularization and infiltration, and accelerating intervertebral disc tissue degeneration.

  6. Mechanismen des vaskulären endothelialen Wachstumsfaktors (VEGF) in der klinischen und experimentellen Plastisch-Rekonstruktiven Chirurgie

    Infanger, Manfred

    2010-01-01

    Vascular endothelial growth factor (VEGF) is one of the most potent mediator of vascular regulation in angiogenesis and vascular permeability. Especially in Plastic reconstructive Surgery, the impact of VEGF is important. Our data clearly document that treatment with VEGF is beneficial to the healing in vascular microsurgery. In severe burn injury, VEGF serum level is strongly enhanced and correlated with local and general tissue edema. For tissue engineering in Plastic surgery, simulated whi...

  7. Radiofrequency ablation of liver metastases

    The liver is the second only to lymph nodes as the most common site of metastatic disease irrespective of the primary tumor. Up to 50% of all patients with malignant diseases will develop liver metastases with a significant morbidity and mortality. Although the surgical resection leads to an improvement of the survival time, only approximately 20% of the patients are eligible for surgical intervention. Radiofrequency (RF) ablation represents one of the most important alternatives as well as complementary methods for the therapy of liver metastases. RF ablation can lead in a selected patient group to a palliation or to an increased life expectancy. RF ablation appears either safer (vs. cryotherapy) or easier (vs. laser) or more effective (percutaneous ethanol instillation [PEI]), transarterial chemoembolisation [TACE] in comparison with other minimal invasive procedures. RF ablation can be performed percutaneously, laparoscopically or intraoperatively and may be combined with chemotherapy as well as with surgical resection. Permanent technical improvements of RF systems, a better understanding of the underlying electrophysiological principles and an interdisciplinary approach will lead to a prognosis improvement in patients with liver metastases. (orig.)

  8. Modern Advances in Ablative TPS

    Venkatapathy, Ethiraj

    2013-01-01

    Topics covered include: Physics of Hypersonic Flow and TPS Considerations. Destinations, Missions and Requirements. State of the Art Thermal Protection Systems Capabilities. Modern Advances in Ablative TPS. Entry Systems Concepts. Flexible TPS for Hypersonic Inflatable Aerodynamic Decelerators. Conformal TPS for Rigid Aeroshell. 3-D Woven TPS for Extreme Entry Environment. Multi-functional Carbon Fabric for Mechanically Deployable.

  9. Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction

    Highlights: ► The designer peptide LRKKLGKA could self-assemble into nanofibers. ► Injection of LRKKLGKA peptides could promote the sustained delivery of VEGF. ► Injection of VEGF with LRKKLGKA peptides lead to sufficient angiogenesis. ► Injection of VEGF with LRKKLGKA peptides improves heart function. -- Abstract: Poor vascularization and insufficient oxygen supply are detrimental to the survival of residual cardiomyocytes or transplanted stem cells after myocardial infarction. To prolong and slow the release of angiogenic factors, which stimulate both angiogenesis and vasculogenesis, we constructed a novel self-assembling peptide by attaching the heparin-binding domain sequence LRKKLGKA to the self-assembling peptide RADA16. This designer self-assembling peptide self-assembled into nanofiber scaffolds under physiological conditions, as observed by atomic force microscopy. The injection of designer self-assembling peptides can efficiently provide the sustained delivery of VEGF for at least 1 month. At 4 weeks after transplantation, cardiac function was improved, and scar size and collagen deposition were markedly reduced in the group receiving VEGF with the LRKKLGKA scaffolds compared with groups receiving VEGF alone, LRKKLGKA scaffolds alone or VEGF with RADA16 scaffolds. The microvessel density in the VEGF with LRKKLGKA group was higher than that in the VEGF with RADA16 group. TUNEL and cleaved caspase-3 expression assays showed that the transplantation of VEGF with LRKKLGKA enhanced cell survival in the infarcted heart. These results present the tailor-made peptide scaffolds as a new generation of sustained-release biomimetic biomaterials and suggest that the use of angiogenic factors along with designer self-assembling peptides can lead to myocardial protection, sufficient angiogenesis, and improvement in cardiac function.

  10. Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction

    Guo, Hai-dong [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Cui, Guo-hong; Yang, Jia-jun [Department of Neurology, Shanghai No. 6 People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233 (China); Wang, Cun [Institutes of Biomedical Sciences, Fudan University, Shanghai 200032 (China); Zhu, Jing; Zhang, Li-sheng; Jiang, Jun [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Shao, Shui-jin, E-mail: shaoshuijin@163.com [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer The designer peptide LRKKLGKA could self-assemble into nanofibers. Black-Right-Pointing-Pointer Injection of LRKKLGKA peptides could promote the sustained delivery of VEGF. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides lead to sufficient angiogenesis. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides improves heart function. -- Abstract: Poor vascularization and insufficient oxygen supply are detrimental to the survival of residual cardiomyocytes or transplanted stem cells after myocardial infarction. To prolong and slow the release of angiogenic factors, which stimulate both angiogenesis and vasculogenesis, we constructed a novel self-assembling peptide by attaching the heparin-binding domain sequence LRKKLGKA to the self-assembling peptide RADA16. This designer self-assembling peptide self-assembled into nanofiber scaffolds under physiological conditions, as observed by atomic force microscopy. The injection of designer self-assembling peptides can efficiently provide the sustained delivery of VEGF for at least 1 month. At 4 weeks after transplantation, cardiac function was improved, and scar size and collagen deposition were markedly reduced in the group receiving VEGF with the LRKKLGKA scaffolds compared with groups receiving VEGF alone, LRKKLGKA scaffolds alone or VEGF with RADA16 scaffolds. The microvessel density in the VEGF with LRKKLGKA group was higher than that in the VEGF with RADA16 group. TUNEL and cleaved caspase-3 expression assays showed that the transplantation of VEGF with LRKKLGKA enhanced cell survival in the infarcted heart. These results present the tailor-made peptide scaffolds as a new generation of sustained-release biomimetic biomaterials and suggest that the use of angiogenic factors along with designer self-assembling peptides can lead to myocardial protection, sufficient angiogenesis, and improvement in cardiac function.

  11. A numerical simulation of ablation controlled arcs

    Godin, D.; Trepanier, J.Y. [Ecole Polytechnique, Dept. of Mechanical Engineering, Montreal, PQ (Canada); Eby, S.D. [Ecole Polytechnique, Centre de Recherche en Calcul Applique, Montreal, PQ (Canada); Robin-Jouan, P. [GEC-Alsthom T and D, Villeurbanne, (France)

    1998-09-01

    An approach to model the ablation phenomenon of ablation controlled arcs using computational fluid dynamics was presented. Ablation controlled arcs are found in high voltage electrical equipment such as fuses and circuit-breakers. A qualitative prediction of the ablation level is critical from an industrial point of view because deliberate use of ablation is made to increase the pressure in a circuit-breaker chamber to allow for an efficient extinction when the current returns to zero. The numerical model was validated by comparing results of published experimental data. 7 refs., 10 figs.

  12. Concentrations of VEGF and VEGFR1 in paired tumor arteries and veins in patients with rectal cancer

    Svendsen, Mads N; Lykke, Jakob; Werther, Kim; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    Increased plasma concentrations of vascular endothelial growth factor (sVEGF) are associated with poor prognosis of colorectal cancer patients. The aim was to investigate the contribution of the tumor to plasma concentrations of VEGF and VEGF receptor 1 (VEGFR1). Preoperative blood samples from a...

  13. Collagenase IV plays an important role in regulating hair cycle by inducing VEGF, IGF-1, and TGF-β expression

    Hou C

    2015-09-01

    Full Text Available Chun Hou, Yong Miao, Jin Wang, Xue Wang, Chao-Yue Chen, Zhi-Qi Hu Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China Background: It has been reported that collagenases (matrix metalloproteinase 2 [MMP-2] and matrix metalloproteinase 9 [MMP-9] are associated with hair cycle, whereas the mechanism of the association is largely unknown.Methods: The mice were randomly allocated into four groups: saline, and 5, 10, and 15 nM SB-3CT. Immunohistochemical analysis was employed to examine MMP-2 and MMP-9 protein. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay were performed to determine mRNA and protein levels of VEGF, IGF-1, TGF-β, and GAPDH. Growing hair follicles from anagen phase III–IV were scored based on hematoxylin and eosin staining. Hair regrowth was also evaluated.Results: Results showed that mRNA expressions of enzymes changed with a peak at late anagen and a trough at telogen after depilation. Immunostaining showed that the highest expression of MMP-2 was more than that of MMP-9, and the highest expression of enzymes changed during anagen. The localizations of MMP-2 changed from dermal papilla, keratinocyte strand, out of root sheath, and basal plate at early anagen, to hair bulb, inner root sheath, and outer root sheath at late anagen. The localization of MMP-9 changed from partial keratinocyte to dermal papilla at early anagen and to outer root sheath at late anagen. VEGF, IGF-1, and TGF-β have been shown to regulate hair growth. We found mRNA and protein expressions of VEGF and IGF-1 fluctuated with a peak at anagen and a decrease at catagen to telogen. In contrast, mRNA and protein expressions of TGF-β changed with highest and lowest levels at anagen and telogen, respectively. With selective inhibitor of collagenase IV, SB-3CT, mice showed significant suppressed hair growth and decreased expression of VEGF, IGF-1

  14. VEGF-A and its isoform VEGF121 mRNA expression measured by quantitative real-time RT-PCR. Correlation with F-18 FDG uptake and aggressiveness of lung adenocarcinoma. Preliminary study

    The objective of this study was to investigate the correlation of vascular endothelial growth factor (VEGF) A and its isoform VEGF121 mRNA expression with F-18 fluorodeoxyglucose (FDG) uptake and aggressiveness in lung adenocarcinoma. Twenty-three patients with lung adenocarcinoma underwent FDG positron emission tomography (PET) before surgery. As semi-quantitative analysis for FDG uptake, partial volume corrected standardized uptake value (PVC-SUV) of the tumor was calculated. Total RNA from lung adenocarcinoma tissue was prepared from the frozen specimens. Using the real-time reverse transcription polymerase chain reaction method, we analyzed the mRNA level of VEGF-A and VEGF-A isoform VEGF121 mRNA level. 18S ribosomal RNA was used as an endogenous control. VEGF-A and VEGF121 mRNA levels had significantly positive correlation with PVC-SUV in lung adenocarcinoma (r=0.477, p=0.021, r=0.539, p=0.008, respectively), while they were not correlated with tumor size (≤3 or >3 cm). VEGF-A and VEGF121 mRNA levels of the low FDG uptake group were significantly lower than those of the high FDG uptake group (p=0.005 and p=0.004, respectively). FDG uptake (PCV-SUV) of aggressive lung adenocarcinoma was higher than that of non-aggressive lung adenocarcinoma (p=0.01). VEGF-A and VEGF121 mRNA levels of aggressive lung adenocarcinoma were higher than those of non-aggressive lung adenocarcinoma (p=0.0001 and p=0.0001, respectively). VEGF-A and VEGF121 mRNA levels may correlate with FDG uptake and aggressiveness in lung adenocarcinoma. These findings support the hypothesis that VEGF-A and VEGF121 may help in predicting the outcome in patients with lung adenocarcinoma. (author)

  15. Vascular endothelial growth factor B (VEGF-B is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease

    Zhang Shiling

    2009-12-01

    Full Text Available Abstract Parkinson's disease (PD results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1 We challenged rat midbrain cultures with rotenone (20 nM, a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B was evident, while vascular endothelial growth factor A (VEGF-A levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using β-actin as the internal standard. (2 We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone. VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a

  16. Post-radiation increase in VEGF enhances glioma cell motility in vitro

    Glioblastoma multiforme (GBM) is among the most lethal of all human tumors, with frequent local recurrences after radiation therapy (RT). The mechanism accounting for such a recurrence pattern is unclear. It has classically been attributed to local recurrence of treatment-resistant cells. However, accumulating evidence suggests that additional mechanisms exist that involve the migration of tumor or tumor stem cells from other brain regions to tumor bed. VEGFs are well-known mitogens and can be up-regulated after RT. Here, we examine the effect of irradiation-induced VEGF on glioma cell motility. U251 and LN18 cell lines were used to generate irradiated-conditioned medium (IR-CM). At 72 h after irradiation, the supernatants were harvested. VEGF level in IR-CM was quantified by ELISA, and expression levels for VEGF mRNA were detected by RT-PCR. In vitro cancer cell motility was measured in chambers coated with/without Matrigel and IR-CM as a cell motility enhancer and a VEGF antibody as a neutralizer of VEGF bioactivity. Immunoblots were performed to evaluate the activity of cell motility-related kinases. Proliferation of GBM cells after treatment was measured by flow cytometry. Irradiation increased the level of VEGF mRNA that was mitigated by pre-RT exposure to Actinomycin D. U251 glioma cell motility (migration and invasion) was enhanced by adding IR-CM to un-irradiated cells (174.9 ± 11.4% and 334.2 ± 46% of control, respectively). When we added VEGF antibody to IR-CM, this enhanced cell motility was negated (110.3 ± 12.0% and 105.7 ± 14.0% of control, respectively). Immunoblot analysis revealed that IR-CM increased phosphorylation of VEGF receptor-2 (VEGFR2) secondary to an increase in VEGF, with a concomitant increase of phosphorylation of the downstream targets (Src and FAK). Increased phosphorylation was mitigated by adding VEGF antibody to IR-CM. There was no difference in the mitotic index of GBM cells treated with and without IR-CM and VEGF. These

  17. Microwave Ablation Compared with Radiofrequency Ablation for Breast Tissue in an Ex Vivo Bovine Udder Model

    Purpose: To compare the effectiveness of microwave (MW) ablation with radiofrequency (RF) ablation for treating breast tissue in a nonperfused ex vivo model of healthy bovine udder tissue. Materials and Methods: MW ablations were performed at power outputs of 25W, 35W, and 45W using a 915-MHz frequency generator and a 2-cm active tip antenna. RF ablations were performed with a bipolar RF system with 2- and 3-cm active tip electrodes. Tissue temperatures were continuously monitored during ablation. Results: The mean short-axis diameters of the coagulation zones were 1.34 ± 0.14, 1.45 ± 0.13, and 1.74 ± 0.11 cm for MW ablation at outputs of 25W, 35W, and 45W. For RF ablation, the corresponding values were 1.16 ± 0.09 and 1.26 ± 0.14 cm with electrodes having 2- and 3-cm active tips, respectively. The mean coagulation volumes were 2.27 ± 0.65, 2.85 ± 0.72, and 4.45 ± 0.47 cm3 for MW ablation at outputs of 25W, 35W, and 45W and 1.18 ± 0.30 and 2.29 ± 0.55 cm3 got RF ablation with 2- and 3-cm electrodes, respectively. MW ablations at 35W and 45W achieved significantly longer short-axis diameters than RF ablations (P < 0.05). The highest tissue temperature was achieved with MW ablation at 45W (P < 0.05). On histological examination, the extent of the ablation zone in MW ablations was less affected by tissue heterogeneity than that in RF ablations. Conclusion: MW ablation appears to be advantageous with respect to the volume of ablation and the shape of the margin of necrosis compared with RF ablation in an ex vivo bovine udder.

  18. Cooperation between HMGA1 and HIF-1 Contributes to Hypoxia-Induced VEGF and Visfatin Gene Expression in 3T3-L1 Adipocytes.

    Messineo, Sebastiano; Laria, Anna Elisa; Arcidiacono, Biagio; Chiefari, Eusebio; Luque Huertas, Raúl M; Foti, Daniela P; Brunetti, Antonio

    2016-01-01

    The architectural transcription factor high-mobility group AT-hook 1 (HMGA1) is a chromatin regulator with implications in several biological processes, including tumorigenesis, inflammation, and metabolism. Previous studies have indicated a role for this factor in promoting the early stages of adipogenesis, while inhibiting adipocyte terminal differentiation, and decreasing fat mass. It has been demonstrated that hypoxia - through the hypoxia-inducible factor 1 (HIF-1) - plays a major role in triggering changes in the adipose tissue of the obese, leading to inhibition of adipocyte differentiation, adipose cell dysfunction, inflammation, insulin resistance, and type 2 diabetes. To examine the possible cooperation between HMGA1 and HIF-1, herein, we investigated the role of HMGA1 in the regulation of Visfatin and VEGF, two genes normally expressed in adipose cells, which are both responsive to hypoxia. We demonstrated that HMGA1 enhanced Visfatin and VEGF gene expression in human embryonic kidney (HEK) 293 cells in hypoxic conditions, whereas HMGA1 knockdown in differentiated 3T3-L1 adipocytes reduced these effects. Reporter gene analysis showed that Visfatin and VEGF transcriptional activity was increased by the addition of either HMGA1 or HIF-1 and even further by the combination of both factors. As demonstrated by chromatin immunoprecipitation in intact cells, HMGA1 directly interacted with the VEGF gene, and this interaction was enhanced in hypoxic conditions. Furthermore, as indicated by co-immunoprecipitation studies, HMGA1 and HIF-1 physically interacted with each other, supporting the notion that this association may corroborate a functional link between these factors. Therefore, our findings provide evidence for molecular cross-talk between HMGA1 and HIF-1, and this may be important for elucidating protein and gene networks relevant to obesity. PMID:27445976

  19. Vascular endothelial growth factor (VEGF and monocyte chemoattractant protein (MCP-1 levels unaltered in symptomatic atherosclerotic carotid plaque patients from North India

    Dheeraj eKhurana

    2013-04-01

    Full Text Available We aimed to identify the role of vascular endothelial growth factor(VEGF and monocyte chemoattractant protein(MCP-1 as a serum biomarker of symptomatic carotid atherosclerotic plaque in North Indian population. Individuals with symptomatic carotid atherosclerotic plaque have high risk of ischemic stroke. Previous studies from western countries have shown an association between VEGF and MCP-1 levels and the incidence of ischemic stroke. In this study, venous blood from 110 human subjects was collected, 57 blood samples of which were obtained from patients with carotid plaques, 38 neurological controls without carotid plaques and another 15 healthy controls who had no history of serious illness. Serum VEGF and MCP-1 levels were measured using commercially available enzyme-linked immunosorbent assay(ELISA. We also correlated the data clinically and carried out risk factor analysis based on the detailed questionnaire obtained from each patient. For risk factor analysis, a total of 70 symptomatic carotid plaque cases and equal number of age and sex matched healthy controls were analyzed. We found that serum VEGF levels in carotid plaque patients did not show any significant change when compared to either of the controls. Similarly, there was no significant upregulation of monocyte chemoattractant protein-1 in the serum of these patients. The risk factor analysis revealed that hypertension, diabetes, and physical inactivity were the main correlates of carotid atherosclerosis(p<0.05. Prevalence of patients was higher residing in urban areas as compared to rural region. We also found that patients coming from mountaineer region were relatively less vulnerable to cerebral atherosclerosis as compared to the ones residing at plain region. We conclude that the pathogenesis of carotid plaques may progress independent of these inflammatory molecules. In parallel, risk factor analysis indicates hypertension, diabetes and sedentary lifestyle as the most

  20. Role of VEGF in the growth and metastasis of a murine bladder carcinoma

    WANG Feng; WU Jihong; TIAN Yuhua; CHEN Xiafang; HU Honghui; WU Wensen; LI Chuanyuan; HUANG Qian

    2003-01-01

    Bladder transitional cell carcinoma is the most common form of carcinoma in the urinary system. Although overexpression of VEGF has been identified in tissue, serum, and urine of patients with bladder cancer, the role of VEGF in transitional cell carcinoma of the bladder has not been clearly elucidated. Here, we dissected the effect of VEGF during bladder tumor growth and progression by modifying a BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine) induced mouse bladder transitional cell carcinoma cell line BTT-T739 by stable transfection of antisense VEGF121 cDNA. The transfection resulted in more than 80% reduction in VEGF production. The growth of the transduced tumor cells in vitro was not affected, however, these cells formed small or no tumors in vivo. Even in the tumors formed, there were mini- mal vascularization, extensive necrosis and longer latency compared to those formed by parental cells. The permeability of tumor vasculature and metastatic tumor growth were also significantly suppressed in antisense VEGF cDNA trans- fected cells. In addition, the transfer of anti-angiogenic gene in a combination of sFlk-1 and ExTek with electroporation can suppress the tumor growth efficiently. Taken together, these results demonstrated that VEGF plays an important role in bladder tumor angiogenesis and angiogenesis plays an important role in bladder tumor growth and metastasis.

  1. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

    The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases

  2. VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

    This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

  3. Association of Chemerin and Vascular Endothelial Growth Factor (VEGF) with Diabetic Nephropathy.

    Lin, Shuhua; Teng, Jian; Li, Jixia; Sun, Fang; Yuan, Dong; Chang, Jing

    2016-01-01

    BACKGROUND Diabetic nephropathy (DN) is a common complication of diabetes, caused by diabetic microvascular lesions. The pathogenesis of DN is complicated, involving genetics, physics, chemistry, and environmental factors. Chemerin is a fat cell factor that participates in regulating inflammation. Vascular endothelial growth factor (VEGF) promotes vascular endothelial cell proliferation, differentiation, and angiogenesis. The relationship role of Chemerin and VEGF in DN is not fully understood. MATERIAL AND METHODS SD rats were randomly divided into 2 groups: the control group and the DN group. Streptozotocin was used to construct the DN model. Serum creatinine (Scr), blood urea nitrogen (BUN), and urine microalbumin (UAlb) were detected. Real-time PCR and Western blot were used to test Chemerin and VEGF mRNA and protein expression in kidney tissue. ELISA was performed to test TGF-β1, TNF-α, and INF-γ levels. The correlation of Chemerin and VEGF with renal function and inflammatory factors was analyzed. RESULTS DN group rats showed obviously increased Scr and BUN levels, and elevated TGF-β1, TNF-α, and INF-γ secretion (P<0.05). Compared with controls, Chemerin and VEGF were clearly overexpressed in the DN group (P<0.05). Chemerin and VEGF expression were positively correlated with inflammatory factors and renal function. CONCLUSIONS Chemerin and VEGF play important roles in DN by regulating inflammatory factors and renal function. They may be treated as indicators of DN. PMID:27612613

  4. Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis

    Sakkas Lazaros

    2009-05-01

    Full Text Available Abstract Background The association between systemic sclerosis and pulmonary arterial hypertension (PAH is well recognized. Vascular endothelial growth factor (VEGF has been reported to play an important role in pulmonary hypertension. The aim of the present study was to examine the relationship between systolic pulmonary artery pressure, clinical and functional manifestations of the disease and serum VEGF levels in systemic sclerosis. Methods Serum VEGF levels were measured in 40 patients with systemic sclerosis and 13 control subjects. All patients underwent clinical examination, pulmonary function tests and echocardiography. Results Serum VEGF levels were higher in systemic sclerosis patients with sPAP ≥ 35 mmHg than in those with sPAP LCO were independent predictors of systolic pulmonary artery pressure. Conclusion Serum VEGF levels are increased in systemic sclerosis patients with sPAP ≥ 35 mmHg. The correlation between VEGF levels and systolic pulmonary artery pressure may suggest a possible role of VEGF in the pathogenesis of PAH in systemic sclerosis.

  5. Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

    Dong Hyun Jo

    Full Text Available Anti-vascular endothelial growth factor (VEGF agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

  6. Experimental studies of a vaccine formulation of recombinant human VEGF antigen with aluminum phosphate

    Pérez Sánchez, Lincidio; Morera Díaz, Yanelys; Bequet-Romero, Mónica; Ramses Hernández, Gerardo; Rodríguez, Yadira; Castro Velazco, Jorge; Puente Pérez, Pedro; Ayala Avila, Marta; Gavilondo, Jorge V

    2015-01-01

    CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen. PMID:25891359

  7. Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike?

    Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF)-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States), VEGF receptors (eg, ramucirumab), and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors). The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012), using search terms including, but not limited to: “bevacizumab,” “aflibercept,” “ramucirumab,” and “IMC-18F1.” Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking

  8. VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

    Sun, Jinqiao, E-mail: jinqiao1977@163.com [Institute of Pediatrics, Children' s Hospital of Fudan University (China); Sha, Bin [Department of Neonatology, Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Zhou, Wenhao, E-mail: zhou_wenhao@yahoo.com.cn [Department of Neonatology, Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Yang, Yi [Institute of Pediatrics, Children' s Hospital of Fudan University (China)

    2010-03-26

    This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

  9. VEGF and VEGFR-2 (KDR) internalization is required for endothelial recovery during wound healing

    Vascular endothelial growth factor (VEGF) receptor activation regulates endothelial cell (EC) survival, migration and proliferation. Recently, it was suggested the cross-talk between the VEGF receptors-1 (FLT-1) and -2 (KDR) modulated several of these functions, but the detailed molecular basis for such interactions remained unexplained. Here we demonstrate for the first time that VEGF stimulation of EC monolayers induced a rapid FLT-1-mediated internalization of KDR to the nucleus, via microtubules and the endocytic pathway, internalization which required the activation of PI 3-kinase/AKT. KDR deletion mutants were generated in several tyrosine residues; in these, VEGF-induced KDR internalization was impaired, demonstrating this process required activation (phosphorylation) of the receptor. Furthermore, we demonstrate that in vitro wounding of EC monolayers leads to a rapid and transient internalization of VEGF + KDR to the nucleus, which is essential for monolayer recovery. Notably, FLT-1 blockade impedes VEGF and KDR activation and internalization, blocking endothelial monolayer recovery. Our data reveal a previously unrecognized mechanism induced by VEGF on EC, which regulates EC recovery following wounding, and as such indicate novel targets for therapeutic intervention

  10. Anti-Human VEGF Repebody Effectively Suppresses Choroidal Neovascularization and Vascular Leakage

    Hwang, Da-Eun; Ryou, Jeong-Hyun; Oh, Jong Rok; Han, Jung Woo; Park, Tae Kwann; Kim, Hak-Sung

    2016-01-01

    Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among people over the age of 60. Vascular endothelial growth factor (VEGF) plays a major role in pathological angiogenesis in AMD. Herein, we present the development of an anti- human VEGF repebody, which is a small-sized protein binder consisting of leucine-rich repeat (LRR) modules. The anti-VEGF repebody selected through a phage-display was shown to have a high affinity and specificity for human VEGF. We demonstrate that this repebody effectively inhibits in vitro angiogenic cellular processes, such as proliferation and migration, by blocking the VEGF-mediated signaling pathway. The repebody was also shown to have a strong suppression effect on choroidal neovascularization (CNV) and vascular leakage in vivo. Our results indicate that the anti-VEGF repebody has a therapeutic potential for treating neovascular AMD as well as other VEGF-involved diseases including diabetic retinopathy and metastatic cancers. PMID:27015541