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Angiogenic Mediator (angiogenic + mediator)
Selected AbstractsTie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor ,,induced angiogenesis in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 9 2003Laura M. DeBusk Objective Rheumatoid arthritis (RA) is an inflammatory disease and an angiogenic disease. However, the molecular mechanisms promoting angiogenesis in RA are not clearly identified. Our objective was to study the role of an endothelium-specific receptor tyrosine kinase, Tie2, in angiogenesis of inflammatory arthritis. Methods Expression of Tie2 and its ligand, angiopoietin 1 (Ang1), in human synovium was examined by immunohistochemistry and Western blot. A novel synovium vascular window model was established to study the role of Tie2 in angiogenesis in vivo. Primary cultured endothelial cells and synoviocytes were used to study tumor necrosis factor , (TNF,),induced Tie2 and Ang1 expression. Results Tie2 was implicated in pathologic angiogenesis. We observed that Tie2 and Ang1 were elevated in human RA synovium. Using a novel collagen-induced arthritis synovial window model, we demonstrated that Tie2 signaling regulated arthritis angiogenesis in vivo. We also showed that Tie2 mediated TNF,-induced angiogenesis in a mouse cornea assay. In addition, we observed that TNF, can regulate Tie2 activation in multiple ways that may involve interactions between endothelial cells and synoviocytes. TNF, up-regulates Tie2 in endothelial cells through nuclear factor ,B, and it up-regulates Ang1 in synoviocytes. These findings suggest paracrine regulation of angiogenesis between endothelial cells and synoviocytes. Conclusion This study demonstrates that Tie2 regulates angiogenesis in inflammatory synovium. Tie2 signaling is an important angiogenic mediator that links the proinflammatory cytokine TNF, to pathologic angiogenesis. [source] Hypoxia-induced production of stromal cell,derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblastsARTHRITIS & RHEUMATISM, Issue 10 2002Carol Hitchon Objective Stromal cell,derived factor 1 (SDF-1; or, CXCL12) is a potent chemotactic and angiogenic factor that has been proposed to play a role in the recruitment of lymphocytes into rheumatoid arthritis (RA) synovium. We tested the hypothesis that synovial SDF-1 expression is regulated by cytokine and hypoxic stimulation, the latter being mediated by hypoxia-inducible factor 1, (HIF-1,). These factors regulate the expression of vascular endothelial growth factor (VEGF), itself an important angiogenic mediator. Methods RA and osteoarthritic synovial fibroblasts and whole tissue explants were cultured under normoxic or hypoxic (1% O2) conditions for up to 72 hours in the presence or absence of interleukin-1, (IL-1,), tumor necrosis factor (TNF), or transforming growth factor , (TGF,). Expression of HIF-1,, VEGF, and SDF-1 was detected in synovial tissue and cells by immunohistochemistry and Western blotting. VEGF and SDF-1 expression by cultured synovial fibroblasts was evaluated by reverse transcription,polymerase chain reaction and enzyme-linked immunosorbent assay. Results Immunohistochemistry revealed the presence of HIF-1,, VEGF, and SDF-1 in RA synovium. Patchy expression of HIF-1, was detected primarily in the synovial lining and sublining areas; expression in synovial fibroblasts and in the lining cells of whole synovial tissue explants was markedly augmented by hypoxic culture conditions. Hypoxia enhanced the expression of VEGF and SDF-1 messenger RNA in synovial fibroblasts. The production of VEGF and SDF-1 protein by synovial fibroblasts was augmented by 50% and 132%, respectively, after 24 hours of hypoxia. VEGF production was potently induced by TGF,, and to a lesser extent by IL-1, and TNF, and was further augmented by hypoxia. In contrast, none of the tested cytokines induced SDF-1 production. Conclusion As with VEGF, SDF-1 expression is induced by hypoxia; however, cytokines induce VEGF but not SDF-1. Hypoxic conditions in RA synovium, which are likely to be transient and episodic, may contribute to the persistence of synovitis by inducing VEGF and SDF-1. [source] Osteoblasts stimulated with pulsed electromagnetic fields increase HUVEC proliferation via a VEGF-A independent mechanism,BIOELECTROMAGNETICS, Issue 3 2009Richard A. Hopper Abstract The clinically beneficial effect of low frequency pulsed electromagnetic fields (ELF-PEMF) on bone healing has been described, but the exact mechanism of action remains unclear. A recent study suggests that there is a direct autocrine mitogenic effect of ELF-PEMF on angiogenesis. The hypothesis of this study is that ELF-PEMF also has an indirect effect on angiogenesis by manipulation of vascular endothelial growth factor (VEGF)-A-based paracrine intercellular communication with neighboring osteoblasts. Conditioned media experiments measured fetal rat calvarial cell (FRC) and human umbilical vein endothelial cell (HUVEC) proliferation using tritiated thymidine uptake. We demonstrate that ELF-PEMF (15 Hz, 1.8 mT, for 8 h) has an indirect effect on the proliferation rate of both endothelial cells and osteoblasts in vitro by altering paracrine mediators. Conditioned media from osteoblast cells stimulated with ELF-PEMF increased endothelial proliferation 54-fold, whereas media from endothelial cells stimulated with ELF-PEMF did not affect osteoblast proliferation. We examined the role of the pro-angiogenic mediator VEGF-A in the mitogenic effect of ELF-PEMF-stimulated osteoblast media on endothelial cells. The production of VEGF-A by FRC as measured by ELISA was not changed by exposure to PEMF, and blocking experiments demonstrated that the ELF-PEMF-induced osteoblast-derived endothelial mitogen observed in these studies was not VEGF-A, but some other soluble angiogenic mediator. Bioelectromagnetics 30:189,197, 2009. © 2008 Wiley-Liss, Inc. [source] Granulocyte/macrophage colony-stimulating factor treatment of human chronic ulcers promotes angiogenesis associated with de novo vascular endothelial growth factor transcription in the ulcer bedBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2006F. Cianfarani Summary Background, Granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine with pleiotropic functions, has been successfully employed in the treatment of chronic skin ulcers. The biological effects underlying GM-CSF action in impaired wound healing have been only partly clarified. Objectives, To investigate the effects of GM-CSF treatment of chronic venous ulcers on lesion vascularization and on the local synthesis of the angiogenic factors vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). Methods, Patients with nonhealing venous leg ulcers were treated with intradermal injection of recombinant human GM-CSF, and biopsies were taken at the ulcer margin before and 5 days after administration. Wound vascularization was analysed by immunohistochemistry using antiplatelet endothelial cell adhesion molecule-1/CD31 and anti-,-smooth muscle actin antibodies. VEGF and PlGF transcription was assessed by in situ hybridization. To identify the cell populations transcribing VEGF within the ulcer bed, the VEGF hybridization signal was correlated with the immunostaining for different cell type markers on serial sections. Direct induction of VEGF transcription by GM-CSF was investigated in GM-CSF-treated cultured macrophages and keratinocytes. Results, Blood vessel density was significantly increased in the ulcer bed following GM-CSF treatment. VEGF transcripts were localized in keratinocytes at the ulcer margin both before and after GM-CSF treatment, whereas a VEGF hybridization signal was evident within the ulcer bed only following administration. PlGF mRNA was barely detectable in keratinocytes at the ulcer margin and was not visibly increased after treatment. Unlike VEGF, a specific PlGF hybridization signal could not be detected in cells within the ulcer following GM-CSF administration. Monocytes/macrophages were the main cell population transcribing VEGF after GM-CSF treatment. In vitro analysis demonstrated that VEGF transcription can be directly stimulated by GM-CSF in a differentiated monocytic cell line, but not in keratinocytes. Conclusions, Our data show that increased vascularization is associated with GM-CSF treatment of chronic venous ulcers and indicate that inflammatory cell-derived VEGF may act as an angiogenic mediator of the healing effect of GM-CSF in chronic ulcers. [source] Plausible linkage of hypoxia inducible factor-1, in uterine cervical cancerCANCER SCIENCE, Issue 9 2006Jiro Fujimoto Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with angiogenic transcription factor hypoxia inducible factors (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine cervical cancers. Although there was no significant difference in HIF-1, histoscores and mRNA levels according to histopathological type or lymph node metastasis, HIF-1, histoscores and mRNA levels increased significantly with advancing cancer stages. The prognosis of 30 patients with high HIF-1, in uterine cervical cancers was poor (73% survival), whereas the 24-month survival rate of the other 30 patients with low HIF-1, was 93%. HIF-1, histoscores and mRNA levels were correlated with the levels of the angiogenic factors thymidine phosphorylase and interleukin-8, and HIF-1, might be linked with these factors in cervical cancer tissue. HIF-1, is a candidate for prognostic indicator as an angiogenic mediator in uterine cervical cancer. (Cancer Sci 2006; 97: 861,867) [source] Anti-vascular endothelial growth factor receptor-2 (Flk-1/KDR) antibody suppresses contact hypersensitivityEXPERIMENTAL DERMATOLOGY, Issue 11 2004Hideaki Watanabe Abstract:, The angiogenic mediator vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have been studied extensively in neoplastic disease and some inflammatory conditions. Contact hypersensitivity (CHS) is a prototypic Langerhans' cell-dependent, T-helper (Th) 1 cell-mediated inflammatory skin disease that is now also thought to involve angiogenic mediators. The purpose of our study was to examine the role of angiogenesis and VEGF in CHS. We demonstrated that VEGF production is up-regulated in murine skin after challenge with dinitrofluorobenzene. Administration of a monoclonal antibody directed against the VEGFR-2 (DC101) resulted in a 28.8% decrease in CHS response (P < 0.001). Examination of the DC101-treated mouse skin 24 h after challenge revealed decreases in dermal inflammatory cellular infiltrates and total vessel area. Furthermore, mRNA and protein of the Th1-type cytokine interferon (IFN)-, was significantly down-regulated in skin of DC101-treated animals 24 h after challenge. The results of the study demonstrate that VEGFR-2 blockade significantly reduces vascular enlargement and edema formation and effects IFN-, expression in the skin during challenge in CHS. Our findings suggest that DC101 could function by reducing inflammatory cell migration and hence IFN-, expression during the CHS response. [source] Neovascularization and mast cells with tryptase activity increase simultaneously in human pterygiumJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2007Domenico Ribatti Abstract Mast cells (MC) have been implicated in both normal and pathological angiogenesis, such as that in chronic inflammatory diseases and tumors. This assumption is partially supported by the close structural association between MC and blood vessels and the recruitment of these cells during tumor growth. MC release a number of angiogenic factors among which tryptase, a serine protease stored in MC granules, is one of the most active. In this study, we correlate the extent of angiogenesis with the number of tryptase-reactive MC in tissue fragments from pterygium and normal bulbar conjunctiva investigated by immunohistochemistry, using two murine monoclonal antibodies against the endothelial cell marker CD31 and the MC marker tryptase. Angiogenesis, measured as microvessel density, was highly correlated with MC tryptase-positive cell count in pterygium tissues. These results suggest that the characteristic neovascularization observed in pterygium may be sustained, at least in part, by MC angiogenic mediators, in particular tryptase. [source] | ||||||||||