UMLS:C0003864 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), is a potent microvascular permeability enhancing cytokine and a selective mitogen for endothelial cells. It has been implicated in tumor angiogenesis and ascites fluid accumulation. Since development of the destructive synovial pannus in rheumatoid arthritis (RA) is associated with changes in vascular permeability (synovial fluid accumulation), synovial cell hyperplasia, and angiogenesis, we examined synovial fluids (SFs) and joint tissue for the expression and local accumulation of VPF/VEGF. VPF/VEGF was detected in all of 21 synovial fluids examined and when measured by an immunofluorimetric assay, ranged from 6.9 to 180.5 pM. These levels are biologically significant, since < 1 pM VPF/VEGF can elicit responses from its target cells, endothelial cells. Levels of VPF/VEGF were highest in rheumatoid arthritis fluids (n = 10), with a mean value (+/- SEM) of 59.1 +/- 18.0 pM, vs. 21.4 +/- 2.3 pM for 11 SFs from patients with other forms of arthritis (p = 0.042). In situ hybridization studies that were performed on joint tissues from patients with active RA revealed that synovial lining macrophages strongly expressed VPF/VEGF mRNA, and that microvascular endothelial cells of nearby blood vessels strongly expressed mRNA for the VPF/VEGF receptors, flt-1 and KDR. Immunohistochemistry performed on inflamed rheumatoid synovial tissue revealed that the VPF/VEGF peptide was localized to macrophages within inflamed synovium, as well as to microvascular endothelium, its putative target in the tissue. Together, these findings indicate that VPF/VEGF may have an important role in the pathogenesis of RA.
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PMID:Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. 800 92

The mechanisms involved in the anti-angiogenic actions of the proteasome inhibitors are poorly understood. Here, we report that the gene expression of the VEGF receptor Flt-1 (vascular endothelial growth factor receptor 1) was down-regulated by the reversible proteasome inhibitor MG262 in explant cultures of the developing chicken pecten oculi, a vascular organ consisting of endothelial cells, pericytes, and macrophages. In addition, the inhibitor prevented the induction of Flt-1 by lipopolysaccharide (LPS) in macrophages and down-regulated the expression of Flt-1 after LPS induction. Flt-1 gene expression was also down regulated by MG262 in cultures of human microvascular endothelial cells. Interestingly, a transcript of Flt-1, coding for a soluble form of the receptor (sFlt-1) with anti-angiogenic properties, was not down-regulated in the same extent. Only a small decrease in the expression of VEGF and Ang-2 was detected in the pecten oculi upon inhibition of the proteasome, while no major changes were observed in the expression of other angiogenic molecules, such as KDR or Ang-1. Since recent experiments have demonstrated the importance of anti-Flt-1 therapy in the inhibition of tumor angiogenesis, retinal angiogenesis, arthritis, and atherosclerosis (Luttun et al. [2002]: Nat Med 8:831-840), our observation on down-regulation of Flt-1 in microvascular endothelial cells and macrophages by MG262 supports the postulated role of the proteasome inhibitors as potential candidates for therapeutic modulation of angiogenesis and inflammation.
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PMID:Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262. 1289 12

Rheumatoid arthritis (RA) is a chronic destructive musculo-skeletal disorder, associated with thickening of the synovial membrane lining the joints, inflammation and hyperproliferation of synovial cells, as well as a pro-inflammatory cytokine cascade, leukocyte infiltration, and tissue damage and bone resorption. An early event in RA is an alteration in blood vessel density and prominent neovascularisation. The hyperplasia of the synovium necessitates a compensatory increase in the number of blood vessels to nourish and oxygenate the tissue. However, angiogenesis may not keep pace with synovial proliferation, leading to regions of hypoperfusion and hypoxia. VEGF, a potent endothelial cell mitogen, is expressed in RA synovium and elevated in the serum of RA patients. We have reported that dissociated RA synovial membrane cells spontaneously secrete VEGF, and that release of VEGF by these cells is upregulated by cytokines and hypoxia. In a murine model of RA, VEGF is released from synovial cells isolated from the knees of arthritic but not healthy mice, and the extent of VEGF production correlates with the severity of arthritis. VEGF thus appears to play a key role in mediating alterations in synovial vessel density in arthritis. As a consequence, RA may be a potential target for anti-angiogenic therapy, and targeting VEGF may prove to be especially beneficial.
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PMID:Angiogenesis in arthritis: role in disease pathogenesis and as a potential therapeutic target. 1451 50

The angiogenic factor VEGF promotes synovitis and bone erosion in rheumatoid arthritis (RA). Previously, we have demonstrated that VEGF expression correlates with disease severity in RA patients and in murine collagen-induced arthritis (CIA). In this study, we adopted an adenoviral gene delivery system expressing soluble VEGF receptor 1 (sFlt-1) to further study the role of VEGF in CIA. Arthritis was induced in DBA/1 mice by injection of bovine collagen. Adenoviruses expressing human soluble VEGF receptor 1 (AdvsFlt-1), or without transgene (Adv0), were injected intravenously on the first day of arthritis. We found that disease severity and paw swelling were significantly suppressed in mice receiving AdvsFlt-1, when compared to untreated or Adv0-treated mice. Expression of sFlt-1 peaked 24 h after injection, with protein detectable in the liver, synovial issue and serum, but rapidly decreased by 72 h. The effect of sFlt-1 expression on signs of disease was paralleled by reduced joint destruction and decreased expression of the vascular marker von Willebrand factor. In summary, adenoviral delivery of human soluble VEGF receptor type 1 significantly suppressed disease activity in CIA. The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA.
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PMID:Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. 1452 19

The important role of angiogenesis for the pathogenesis of most tumors has gained much interest into the mechanisms of new vessel formation during recent years. Hypoxia induces angiogenesis via stabilization of the transcription factor HIF-1alpha. After dimerization of HIF-1alpha with HIF-1beta/ARNT, HIF-1 binds to the hypoxia-responsive elements in the regulatory regions of proangiogenic molecules such as VEGF. Hypoxia-mediated angiogenesis also plays a part in the pathogenesis of rheumatoid arthritis. For instance, intraarticular application of the angiostatic molecule angiostatin reduces the severity of collagen-induced arthritis in mice. Moreover, recent data indicate that the expression of HIF-1alpha in myeloid cells is important for the initiation of the inflammatory infiltrate in rheumatoid arthritis. In contrast to rheumatoid arthritis, the therapeutic goal in systemic sclerosis (SSc) is the formation of new vessels rather than the inhibition of angiogenesis. Surprisingly, several proangiogenic factors such as VEGF or MCP-1 (CCL-2) are overexpressed in the skin of patients with SSc despite the reduction in the capillary density. The role of these findings for the defective angiogenesis in SSc is currently investigated in our laboratory.
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PMID:[Hypoxia and angiogenesis in rheumatic diseases]. 1464 91

Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.
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PMID:Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library. 1519 67

The aim of our study was to test the hypothesis that differences in behavioral characteristics are linked to severity of arthritis in association with neuro-endocrine and immune reactivity in an inbred strain of rats. Lewis rats were selected as high-active (HA) and low-active (LA) animals based on their exploratory activity in the open field. Subsequently, adjuvant-arthritis (AA) was induced in both groups. We observed no differences in the severity of inflammation as determined by paw swelling and redness. However, LA and HA animals differed in the severity of bone destruction as determined on radiographs taken on day 30 after induction of AA. LA rats had more osteoporosis, periostal new bone formation, and bone destruction than HA rats. There were no differences between HA and LA rats in corticosterone response after acute or chronic immune challenge. Splenocytes of LA rats had a lower mitogen-induced IL-10 and IFNgamma production during AA. Histological examination revealed more intense factor VIII staining in arthritic joints of LA animals, indicating more pronounced synovial angiogenesis. In addition, LA rats had higher plasma VEGF, an important angiogenic factor. Expression of RANKL, a crucial factor promoting bone resorption, was also higher in joints of LA animals. Our data demonstrate that activity in the open field, a behavioral trait, is associated with the severity of bone destruction in AA. Lower production of bone-protective cytokines and a higher rate of angiogenesis leading to more synovial proliferation may be responsible for the more severe joint destruction in LA animals.
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PMID:Individual differences in behavior of inbred Lewis rats are associated with severity of joint destruction in adjuvant-induced arthritis. 1533 Nov 19

Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations harbor genetic variations that alter angiogenesis. Some of these changes result in Mendelian traits of variable penetrance, with telangiectasia being a common symptom. Other more subtle variations exist, with promoter variations in the VEGF gene being of particular interest. Genetic diversity in angiogenesis-regulating genes has been linked to increased susceptibility to multiple angiogenesis-dependent diseases in humans. These diseases include cancer, arthritis, atherosclerosis, and cardiovascular disease, endometriosis, diabetic retinopathy, retinopathy of prematurity, psoriasis, and sarcoidosis. Also, multiple disturbances in pregnancy including miscarriage, spontaneous preterm delivery, and severe pre-eclampsia have been linked to alterations in angiogenesis-regulating genes. Present efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Ongoing mapping studies have identified multiple loci that control angiogenic responsiveness in several mouse models. Genetic alterations responsible for discrete angiogenic alterations will then be studied in appropriate mouse disease models.
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PMID:The effect of genetic diversity on angiogenesis. 1632 83

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.
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PMID:Regulation of angiogenesis by the kallikrein-kinin system. 1684 60

Background. Angiogenesis is involved in rheumatoid arthritis (RA) leading to leucocyte recruitment and inflammation in the synovium. Furthermore, synovial inflammation itself further potentiates endothelial proliferation and angiogenesis. In this study, we aimed at evaluating the reciprocical relationship between synovial inflammation and angiogenesis in a RA model, namely collagen-induced arthritis (CIA). Methods. CIA was induced by immunization of DBA/1 mice with collagen type II in adjuvant. Endothelial cells were detected using a GSL-1 lectin-specific immunohistochemical staining on knee joint sections. Angiogenesis, clinical scores and histological signs of arthritis were evaluated from the induction of CIA until the end of the experiment. Angiogenesis was quantified by counting both the isolated endothelial cells and vessels stained on each section. To evaluate the effect of increased angiogenesis on CIA, VEGF gene transfer was performed using an adeno-associated virus encoding VEGF (AAV-VEGF), by intra-muscular or intra-articular injection in mice with CIA. Results. We showed an increase in synovial angiogenesis from day 6 to day 55 after CIA induction, and, moreover, joint vascularization and clinical scores of arthritis were correlated (p < 0.0001, r = 0.61). Vascularization and histological scores were also correlated (p = 0.0006, r = 0.51). Systemic VEGF overexpression in mice with CIA was followed by an aggravation of arthritis as compared to AAV-lacZ control group (p < 0.0001). In contrast, there was no difference in clinical scores between control mice and mice injected within the knee with AAV-VEGF, even if joint vascularization was higher in this group than in all other groups (p = 0,05 versus non-injected group). Intra-articular AAV-VEGF injections induced more severe signs of histological inflammation and bone destruction than AAV-Lac Z or no injection. Conclusion. Angiogenesis and joint inflammation evolve in parallel during collagen-induced arthritis. Furthermore, this work shows that exogenous VEGF can aggravate CIA. It is direct evidence that the increase in joint vascularization leads to an exacerbation of arthritis. Taken together, these results emphasize the role of angiogenesis in inflammatory arthritis. It also suggests an early involvement of angiogenesis in joint inflammation.
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PMID:Relationship between angiogenesis and inflammation in experimental arthritis. 1719 41

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