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Expression of vascular endothelial growth factor isoforms and their receptors Flt‐1, KDR, and neuropilin‐1 in synovial tissues of rheumatoid arthritis
Author(s) -
Ikeda Mika,
Hosoda Yasuhiro,
Hirose Shigemichi,
Okada Yasunori,
Ikeda Eiji
Publication year - 2000
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/1096-9896(2000)9999:9999<::aid-path649>3.0.co;2-e
Subject(s) - neuropilin 1 , vascular endothelial growth factor , angiogenesis , receptor , rheumatoid arthritis , medicine , gene isoform , synovitis , synovial membrane , pathology , neuropilin , immunohistochemistry , endocrinology , immunology , cancer research , biology , vegf receptors , biochemistry , gene
Angiogenesis is an indispensable process in the chronic proliferative synovitis and pannus formation of rheumatoid arthritis (RA). This study examined the expression of vascular endothelial growth factor (VEGF) isoforms and VEGF receptors, Flt‐1, KDR and neuropilin‐1, in RA and osteoarthritis (OA) synovia, and studied the relationship between their expression and the synovial angiogenesis. By RT‐PCR analysis, the isoform VEGF 121 was constitutively expressed in all the RA (17/17 patients) and OA (8/8 patients) synovia. In contrast, the expression of the isoform VEGF 165 was observed in 41% of the RA synovia (7/17 patients), but was undetectable in the OA samples (0/8 patients). The receptor Flt‐1 was almost constitutively expressed in RA (15/17 patients) and OA (8/8 patients) synovia, while the expression of KDR was detected in the synovia of six RA patients (6/17 patients; 35%) but none of the OA patients (0/8 patients). The expression of neuropilin‐1, an isoform‐specific receptor for VEGF 165 which enhances the binding of VEGF 165 to KDR, was also up‐regulated in the same RA synovia that expressed KDR. Furthermore, there was a close correlation between the expression of isoform VEGF 165 and that of its receptors KDR and neuropilin‐1. Morphometric analysis demonstrated that the vascular density is significantly higher in the RA synovial tissues with expression of VEGF 165 , KDR, and neuropilin‐1 than in those without their expression ( p <0.01). In situ hybridization and immunohistochemical studies indicated that the cells expressing VEGF are macrophage‐like synovial lining cells and spindle‐shaped cells in the sublining cell layer. These results suggest that the selective up‐regulation of the isoform VEGF 165 and its signalling via KDR and neuropilin‐1 play an important role in the synovial angiogenesis which occurs in RA. Copyright © 2000 John Wiley & Sons, Ltd.