Expression of vascular endothelial growth factor isoforms and their receptors Flt‐1, KDR, and neuropilin‐1 in synovial tissues of rheumatoid arthritis

Abstract

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-speci®c 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 signi®cantly 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.

Endothelial precursor cells in the synovial tissue of patients with rheumatoid arthritis and osteoarthritis

“…VEGFR-2 mediates the major growth and permeability actions of VEGF, the most critical driver of vascular formation under various physiologic and pathologic conditions (15,16,27,28 165 and its signaling via VEGFR-2 can play an important role in synovial angiogenesis and vasculogenesis in RA. Herein we have shown that high levels of VEGFR-2 were expressed on the surface of two populations of precursor cells in synovial tissues of RA and OA patients, one population being CD34ϩ and the other being CD133ϩ.…”

Role of placenta growth factor and its receptor flt‐1 in rheumatoid inflammation: A link between angiogenesis and inflammation

“…Of interest, it has been suggested that flt-1 induces pathologic angiogenesis without affecting physiologic angiogenesis (18,19), indicating that it could be an ideal therapeutic target for several angiogenic disorders. Expression of flt-1 is increased in inflamed synovium (20). In addition, antiflt-1 antibody has been found to suppress joint destruction in an animal model of RA (21).…”

Angiogenic role for glycodelin in tumorigenesis

“…By using the primers described, the expected PCR products for each VEGF variant were calculated as 440 bp, 572 bp, 644 bp, and 695 bp for isoforms of 121, 165, 189, and 206, respectively. The primers used for Flt-1 were 5Ј-GATGTTGAGGAAGAGGAGGATT-3Ј (forward) and 5Ј-AAGCTAGTTTCCTGGGGGTATA-3Ј (reverse) (26). The PCR conditions consisted of 30 cycles of denaturation for 1 min at 94°C, annealing for 2 min at 64°C, and extension for 3 min at 72°C; PCR product was analyzed on a 2% agarose gel stained by ethidium bromide.…”