title: The angiogenic pathway "vascular endothelial growth factor/flk-1(KDR)-receptor" in rheumatoid arthritis and osteoarthritis.
abstract: Active angiogenesis, together with an up-regulation of angiogenic factors, is evident in the synovium of both rheumatoid arthritis (RA) and osteoarthritis (OA). The present study assessed, by immunohistochemistry, the microvessel density in the synovium of these arthritides and in normal controls, in relation to the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) and the apoptosis-related proteins bcl-2 and p53. More importantly, using the novel 11B5 MAb, the activated "VEGF/flk-1(KDR)-receptor" microvessel density was assessed. VEGF expression in fibroblasts was diffuse in both RA and OA. Diffuse PD-ECGF expression of fibroblasts was noted in all cases of RA, while fibroblast reactivity was focal in the OA material. The standard microvessel density (sMVD), as assessed with the anti-CD31 monoclonal antibody (MAb), was higher in RA (64+/-12) and in OA (65+/-16) than in normal tissues (52+/-8; p=0.008 and 0.0004, respectively). The activated microvessel density (aMVD), assessed with the 11B5 MAb, was significantly higher in RA (29+/-10) than in OA (17+/-4; p<0.0001) and than in normal tissues (14+/-2; p<0.0001). The "activation ratio" (aMVD/sMVD) was statistically higher in RA (0.46+/-0.17) than in OA and normal synovial tissues, the latter two having a similar ratio (0.28+/-0.08 and 0.26+/-0.03, respectively). Cytoplasmic bcl-2 expression was frequent in the synovial cells of OA, but rare in RA. Nuclear p53 protein accumulation was never observed. It is suggested that the angiogenic pathway VEGF/flk-1(KDR) may play an important role in the pathogenesis of RA and OA. Thus, failure of VEGF/flk-1(KDR) activation, in the presence of increased VEGF expression, may indicate a synovium with an impaired capacity to establish a viable vasculature, consistent with the degenerative nature of OA. On the other hand, the activated angiogenesis in RA shows a functional, still pathologically up-regulated VEGF/flk-1(KDR) pathway. Whether restoration of an impaired VEGF/flk-1(KDR) pathway in OA, or inhibition of this in RA, would prove of therapeutic importance requires further investigation.
authors.affiliation: Department of Pathology, Democritus University of Thrace, P.O. Box 12, Alexandroupolis 68100, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: E
authors.initials: E
authors.lastname: Sivridis
authors.forename: N
authors.initials: N
authors.lastname: Athanassou
authors.forename: E
authors.initials: E
authors.lastname: Zois
authors.forename: P E
authors.initials: PE
authors.lastname: Thorpe
authors.forename: R A
authors.initials: RA
authors.lastname: Brekken
authors.forename: K C
authors.initials: KC
authors.lastname: Gatter
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: I M
authors.initials: IM
authors.lastname: Koukourakis
authors.forename: M I
authors.initials: MI
authors.lastname: Koukourakis
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D013583:Synovial Membrane / Q000098:blood supply* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D019253:Proto-Oncogene Proteins c-bcl-2; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor