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-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.

Intra-articular tissue factor/factor VII complex induces chronic arthritis

“…In agreement with this notion is the ability to up-regulate the expression of vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) by ligating TF receptor [12,24,30]. It has been shown that increased levels of VEGF trigger synovial proliferation [31], stimulate cell migration and adhesion [30]. Up-regulation of the growth factor genes is shown to be independent of thrombin formation.…”

Synovial Hypoxia as a Cause of Tendon Rupture in Rheumatoid Arthritis

“…9,[15][16][17][18]32 This angiogenic drive is clearly responsible for creating the growing pannus within the joint. Yet, the literature shows that despite the growth of extra blood vessels in the inflamed synovium, rheumatoid joints are also hypoxic.…”

Effects and mechanisms of total glucosides of paeony on joint damage in rat collagen-induced arthritis

“…The expression of VEGF 121 is necessary for the normal functioning of the synovial vessels. Isoform VEGF 165 is restricted to the highly vascularized RA synovium, and has a significant correlation with the higher vascular density in RA [31]. It has been shown that synovial macrophages and fibroblasts in arthritic joint can express and secrete VEGF [30,32].…”