Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is much evidence that rheumatoid arthritis is closely linked to angiogenesis. Important angiogenic mediators have been demonstrated in synovium and tenosynovium of rheumatoid joints. VEGF (Vascular Endothelial Growth Factor), expressed in response to soluble mediators such as cytokines and growth factors and its receptors are the best characterized system in the angiogenesis regulation of rheumatoid joints. Moreover, other angiogenic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, endothelial mediator (endoglin) play an important role in angiogenesis in rheumatoid arthritis. On the other hand, endostatin, thrombospondin-1 and -2 are angiogenic inhibitors in rheumatoid arthritis. The persistence of inflammation in rheumatoid joints is a consequence of an imbalance between these inducers and inhibitors of angiogenesis.
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PMID:Angiogenesis in rheumatoid arthritis. 1649 85

Endostatin is an endogenous angiogenesis inhibitor which requires E-selectin for its antiangiogenic activity. The aim of this study was to investigate the expression of endostatin in human choroidal neovascular membranes (CNV) secondary to age-related macular degeneration (AMD) with regard to vascularization and proliferative activity. An interventional case series of 36 patients who underwent removal of CNV were retrospectively investigated. Thirty-six CNV were analyzed by light microscopic immunohistochemistry for the expression of CD34 (endothelial cells, EC), CD105 (activated EC), Ki-67 (cell proliferation), Cytokeratin 18 (epithelial cells), VEGF (vascular endothelial growth factor), E-selectin and endostatin. Donor eyes (n=7) including one with AMD were used as controls. Endostatin immunoreactivity was present in choroidal vessels of five as well as in the retinal pigment epithelium (RPE)-Bruch's membrane complex of two donor eyes without AMD. In one eye with AMD, endostatin was detected in RPE, Bruch's membrane and choroidal vessels. Ninety-two percent (33/36) of CNV disclosed endostatin staining. RPE-Bruch's membrane complex, choroidal vessels and stroma were positive in 50% (18/36), 72% (26/36), and 78% (28/36) of the membranes, respectively. Both control eyes and CNV expressed all the investigated markers except E-selectin being positive only in membranes. Endostatin, an endogenous angiogenesis inhibitor, is expressed in CNV and its therapeutic up-regulation may be a new strategy in the treatment of neovascular AMD.
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PMID:Expression of endostatin in human choroidal neovascular membranes secondary to age-related macular degeneration. 1658 30

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
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PMID:Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. 1669 53

This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous "take rate" in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation.
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PMID:Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo. 1672 21

We investigated the ability of extracellular matrix (ECM) proteins to modulate the response of endothelial cells to both promoters and inhibitors of angiogenesis. Using human dermal microvascular endothelial cells (HDMEC), we found that cells demonstrated different adhesive properties and proliferative responses to the growth factor VEGF depending upon which ECM protein with which they were in contact, with fibronectin having the most impact on VEGF-induced HDMEC proliferation and survival. More importantly, we observed that ECM could modulate the ability of the angiogenic inhibitor endostatin to prevent endothelial cell proliferation, survival and migration. We observed that growth on vitronectin or fibronectin impaired the ability of endostatin to inhibit VEGF-induced HDMEC proliferation to the greatest extent as determined by BrdU incorporation. We found that, following growth on collagen I or collagen IV, endostatin only inhibited VEGF-induced HDMEC proliferation at the highest dose tested (2500 ng/ml). In a similar manner, we observed that growth on ECM proteins modulated the ability of endostatin to induce endothelial cell apoptosis, with growth on collagen I, fibronectin and collagen IV impairing endostatin-induced apoptosis. Interestingly, endostatin inhibited VEGF-induced HDMEC migration following culture on collagen I, collagen IV and laminin, while migration was not inhibited by endostatin following HDMEC culture on other matrices including vitronectin, fibronectin and tenascin-C. These results suggest that different matrix proteins may affect different mechanisms of endostatin inhibition of angiogenesis. Taken together, our results suggest that the ECM may have a profound impact on the ability of angiostatic molecules such as endostatin to inhibit angiogenesis and thus may have impact on the clinical efficacy of such inhibitors.
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PMID:The inhibitory effects of endostatin on endothelial cells are modulated by extracellular matrix. 1672 39

The role of angiostatic factors, including endostatin, in regulating physiological angiogenesis is poorly understood. We used normal adult rats under physiological resting conditions to examine the relationship between tissue endostatin, VEGF, and capillary density (CD) in the heart (high metabolic activity) versus the skeletal muscle (relatively low metabolic activity). The heart (left ventricle, LV) and skeletal muscle (anterior tibialis, AT) were dissected from 12-week-old male Sprague-Dawley rats. Transverse cryosections of LV and AT were stained with FITC-conjugated GS-I-lectin. CD was determined by analysis of randomly acquired digital images of the cryosections using Optimas software. Tissue protein levels of endostatin and VEGF were determined by ELISA assays. Tissue endostatin levels were lower in the LV and higher in the AT (135 +/- 39 vs. 663 +/- 114 pg/mg) and VEGF levels were higher in the LV and lower in the AT (41 +/- 3 vs. 27 +/- 4 pg/mg), respectively (n = 7, P < 0.01). CD in LV and AT were 3632 +/- 428 and 437 +/- 44/mm2, respectively (P < 0.01). We demonstrated that an 8.3-fold greater capillary density is related to a 4.9-fold lower level of tissue endostatin and a 1.5-fold higher level of tissue VEGF in the heart (LV) versus the skeletal muscle (AT) of normal rats under physiological resting conditions. Also, exercise training increased capillary density, decreased tissue endostatin and increased tissue VEGF in the skeletal muscle (AT). These findings suggest that tissue endostatin content correlates inversely with capillary network in the muscle tissues with different metabolic activity, and that tissue endostatin may play a very important role in the metabolic control of angiogenesis under physiological conditions.
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PMID:Tissue endostatin correlates inversely with capillary network in rat heart and skeletal muscles. 1679 8

Myoseverin, a new microtubule-binding molecule, acts reversibly on myoblast proliferation without the cytotoxic effects displayed by nonpurine-based microtubule-disrupting molecules, like taxol, vinblastine, nocodazole, and the colchicines. In this study, we examined the effects of myoseverin on in vitro function of endothelial cells and endothelial progenitor cell differentiation in order to explore the possibility for the application of myoseverin as a reversible antiangiogenic agent. Myoseverin potently inhibited proliferation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner with an IC50 of approximately 8 microM. When myoseverin was removed after treatment for 3 days, all the cells pretreated at a concentration range of 2.5-80 microM resumed the cell growth. It also inhibited VEGF-induced HUVEC migration dose dependently. When mononuclear cells (MNCs) isolated from human cord blood were cultured on fibronectin-coated plates for 7 days, myoseverin decreased the number of adherent cells in a dose-dependent manner with IC50 of approximately 9 microM. It also suppressed the development of ac-LDL uptake ability as well as the expression of endothelial lineage markers, KDR, CD31, and vWF. Finally, it inhibited formation of HUVECs or ex vivo cultivated EPCs into capillary-like structure on Matri-gel and in vivo angiogenesis on the chick chorioallantoic membrane. Therefore, these results suggest that myoseverin can be effectively used for the inhibition of new vessel growth by inhibiting endothelial cell function and differentiation of progenitor cells.
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PMID:Myoseverin is a potential angiogenesis inhibitor by inhibiting endothelial cell function and endothelial progenitor cell differentiation. 1698 74

Angiogenesis is an essential component of ulcer healing since it assures delivery of oxygen and nutrients to the healing site. Previous studies demonstrated increased serum and tissue levels of vascular endothelial growth factor (VEGF, the most potent angiogenic growth factor) in patients with active ulcerative colitis (UC) and animal models of UC. However, there is no explanation why the healing of UC-related mucosal injury is impaired despite increased expression of VEGF. Expression of angiogenesis inhibitors, angiostatin and/or endostatin, in UC has not been determined before. We examined expression of VEGF, angiostatin, and endostatin in two models of experimental UC. The results revealed that in addition to increased VEGF, both endostatin and angiostatin levels were markedly (2-3-folds) increased in colonic mucosa at early stage of experimental UC. This is the first demonstration that colitis triggers increase in angiostatin and endostatin levels. The results may explain why mucosal lesions heal slowly despite increased VEGF levels, and may provide a novel and mechanistic insight into UC.
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PMID:Altered angiogenic balance in ulcerative colitis: a key to impaired healing? 1701 22

Interactions between cancer cells and the tissue microenvironment play an essential role in controlling tumor development and progression. Here, we report that stromal modulation induced by a biodegradable meshwork (Hyalograft 3D) inhibited tumor vascularization and invasion of the locally invasive low-grade malignant human HaCaT-ras II-4 keratinocytes in a surface xenotransplantation assay. The scaffold caused formation of an active granulation tissue that shifted to a fibrotic-type connective tissue with accumulation of myofibroblasts and collagen bundles. Most importantly, in transplants with scaffolds, the epithelial-stromal border was normalized developing an ultrastructurally complete basement membrane (BM) including hemidesmosomes. The observed reversion of the tumor phenotype was not due to decreased tumor cell proliferation but correlated with (i) normalization of epidermal differentiation, (ii) condensation of extracellular matrix (ECM) and (iii) reduction of peritumoral protease activity Furthermore, inhibited invasion was paralleled by eliminated tumor vascularization. This was substantiated by a diminished endothelial VEGF-receptor (VEGFR) expression and, in turn, by a concomitant increase in the ECM components thrombospondin-1 (TSP-1) and endostatin, known to impair angiogenesis. Even in transplants of the metastatic high-grade malignant HaCaT-ras A-5RT3 keratinocytes the anti-invasive effect of the scaffold-modulated stroma prevailed. Tumor vascularization and invasion was reduced and the epithelial tissue partially normalized including formation of stretches of BM. This clearly demonstrates that the scaffold-modulated connective tissue not only blocks tumor invasion but reverts the tumor phenotype. These novel findings underline the controlling function of tumor stroma and open new strategies of cancer therapy by targeting tumor stroma elements.
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PMID:Reversion of tumor phenotype in surface transplants of skin SCC cells by scaffold-induced stroma modulation. 1705 7

Compounds containing amide bond play a pivotal role in various pharmaceutical applications. 2-(2-(2-Ethoxybenzoylamino)-4-chlorophenoxy)-N-(2-ethoxybenzoyl)benzamine 4 is shown to be a potent antiangiogenic agent. In this study, we report the microwave-assisted synthesis, single crystal X-ray structure, and antiangiogenic effect of compound 4 in EAT cell induced angiogenesis. Treatment with compound 4 in vivo demonstrated down regulation of the secretion of VEGF in EAT cells and inhibition of blood vessel formation indicating the potential angioinhibitory effect of the compound in EAT cells.
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PMID:2-(2-(2-Ethoxybenzoylamino)-4-chlorophenoxy)-N-(2-ethoxybenzoyl)benzamine inhibits EAT cell induced angiogenesis by down regulation of VEGF secretion. 1737 84


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