Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue.

Abstract

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.

Quantitation of the changes in vascularity during arthritis in the knee joint of a mouse with a digital image analysis system

“…This was confirms previous preliminary findings in that blood vessels sprouted, particularly between Days 4 and 7 (Buma et al, 2000). The relative avascularity of the synovial membrane during the first few days after the induction of arthritis might induce hypoxia, which is a powerful inducer of angiogenesis (Blake et al, 1989;Fava et al, 1994;Paleolog, 1996;Stevens et al, 1991).…”

“…Particularly in rheumatoid arthritis, the synovium shows a chronic inflammatory reaction, with neovascularization, infiltration of lymphocytes, plasma cells and macrophages. Cells in this tissue that may even grow out as pannus tissue over the surface of the cartilage, produce catabolic factors for cartilage (Ben et al, 1995;Colville-Nash and Scott, 1992;Fava et al, 1994;FitzGerald et al, 1991). The expansion of this hyperplastic synovial tissue is associated with an extensive prolif- eration of blood vessels (Blake et al, 1989;Buma et al, 2000;Colville-Nash and Scott, 1992).…”

Inhibition of interleukin‐1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

“…However, our data indicating that IL-1Ra blocks bFGF-and VEGF-induced angiogenesis in the cornea are particularly intriguing in that increasing evidence suggests that these vascular growth factors play a prominent role in the pathogenesis of RA. For example, VEGF levels in serum (38,39) and synovial fluid (40)(41)(42) are substantially elevated in RA and are correlated with disease activity. Furthermore, VEGF is expressed widely in arthritic joints, especially macrophages and fibroblasts in RA patients (40,43), as well as mice with CIA (25) and rats with AIA (42).…”

“…For example, VEGF levels in serum (38,39) and synovial fluid (40)(41)(42) are substantially elevated in RA and are correlated with disease activity. Furthermore, VEGF is expressed widely in arthritic joints, especially macrophages and fibroblasts in RA patients (40,43), as well as mice with CIA (25) and rats with AIA (42). Significantly, IL-1 induces VEGF expression in cultured fibroblast-like synoviocytes isolated from RA synovial tissue (35,44).…”

Prognostic significance of angiogenesis in human pancreatic cancer

“…VEGF expression increases in response to several stimuli such as hypoxia (Brogi et al, 1996), certain oncogene products including mutant ras genes (Rak et al, 1995) and the overexpression of transforming growth factor (Detmar et al, 1994). In addition to tumour growth and metastasis, the endogenous upregulation of VEGF has been implicated as the basis for the angiogenesis associated with diabetic retinopathy (Aiello et al, 1994), rheumatoid arthritis (Fava et al, 1994), and wound healing (Tsurumi et al, 1997).…”