The role of angiogenesis in rheumatoid arthritis: recent developments
- Northwestern University Medical School and Veteran's Administration Chicago Healthcare System, Lakeside Division, Ward Building 3–315, 303 E Chicago Avenue, Chicago, IL 60611, USA
- Dr Koch ( )
Rheumatoid arthritis (RA) is characterised by synovial tissue leucocyte ingress and angiogenesis, or new blood vessel growth.1-8 The disease is thought to occur as an immunological response to an as yet unidentified antigen. Even in early RA, some of the earliest histological observations are blood vessels.9 A mononuclear infiltrate characterises the synovial tissue along with a luxuriant vasculature. Angiogenesis is integral to formation of the inflammatory pannus and without angiogenesis, leucocyte ingress could not occur.
Angiogenesis is regulated by a complex set of inducers and inhibitors. In this paper we will present representative examples of both angiogenesis inducers and inhibitors that may regulate RA neovascularisation (fig 1). In inflammatory states like RA, angiogenesis inducers outweigh angiogenesis inhibitors.
ENDOGLIN AS AN ANGIOGENIC MEDIATOR
There are a number of angiogenesis inducers that may play a part in RA. Among these are endoglin, an endothelial glycoprotein, which contains an arginine-glycine-aspartic acid (RGD) motif, and also acts as an adhesion molecule.10 11 Endoglin is a receptor for transforming growth factor β. Mice lacking the endoglin gene die from defective vascular development.12 We have shown that endoglin is upregulated in RA synovial endothelial cells compared with normal synovial tissue endothelial cells.13
VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
An angiogenic mediator that has attracted much attention recently is VEGF, which is an endothelial selective growth factor.14 VEGF induces vascular permeability as well.15 In human RA, several groups have described VEGF in the joints and serum of RA patients.16-23 VEGF is inducible by hypoxia, which may occur in the inflamed joint.17 24 Hypoxia inducible factor-1 (HIF-1), which is made of HIF-1α, and hydroxycarbon nuclear translocator (ARNT), contols many transciptional responses to hypoxia by binding to hypoxia response elements of target genes like the VEGF gene.25 …