ab2006

VEGF release is associated with reduced oxygen tensions in experimental inflammatory arthritis

P.J. Etherington², P. Winlove³, P. Taylor, E. Paleolog¹, J.M. Miotla^1,4

¹Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London; ²Unit of Critical Care, NHLI, Royal Brompton Campus Imperial College School of Medicine, London; ³School of Physics, University of Exeter, Exeter; ⁴Endothelial Cell Biology Laboratory, Cancer Research UK, London, UK.

ABSTRACT
Objective
The contribution of local VEGF production and subsequent angiogenesis within the synovial membrane to the propagation of arthritis is unclear. The relationship between synovial oxygenation and blood flow in the development of arthritic disease is unknown. We have therefore measured oxygen levels and perfusion rates in the synovial space in a murine model of arthritis.

Methods
Arthritis was induced in DBA/1 mice by immunisation with type II collagen. Oxygen and perfusion levels were measured polarographically using silver needle microelectrodes within the knee joints prior to and 10 days after the onset of arthritis. In addition, synovial cells were isolated from knee joints of naive, pre-arthritic and arthritic mice.

Results
Onset of arthritis was associated with a marked reduction in synovial oxygen tensions (pO₂). The perfusion rates in naive and arthritic animals were not significantly different: in naive mice, the rate was 0.58 ± 0.11 ml/min/g and in arthritic joints, 0.64 ± 0.17 ml/min/g. Furthermore, synovial cells isolated from the knee joints of naive animals did not express mRNA for VEGF, but significant levels were detected in cells from non-arthritic mice immunised with collagen. The onset of arthritis was associated with expression of VEGF mRNA and protein, and correlated negatively with pO₂ levels.

Conclusion
These data demonstrate that decreases in intra-articular pO₂ occur in established arthritic conditions and may be the stimulus for local VEGF production. However, perfusion was not increased in arthritic animals and vascular density was unaltered, suggesting that the neovascularisation associated with inflammatory arthritis, is insufficient to restore oxygen homeostasis in the joint.

Key words
Rheumatoid arthritis, vascular endothelial growth factor, collagen-induced arthritis.

Please address correspondence to: Dr Jadwiga M. Miotla, Endothelial Cell Biology Laboratory, Cancer Research UK, PO Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
E-mail: Jadwiga.Miotla@cancer.org.uk