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Vascular Endothelial Growth Factors C and D and Their VEGFR-2 and 3 Receptors in Blood and Lymphatic Vessels in Healthy and Arthritic Synovium KARRI PAAVONEN, JAMI MANDELIN, TAINA PARTANEN, LOTTA JUSSILA, TIAN-FANG LI, ARI RISTIMÄKI, KARI ALITALO, and YRJÖ T. KONTTINEN
ABSTRACT. Methods. Immunohistochemical staining and messenger RNA analysis from control and arthritic synovial membrane specimens. Results. Quantitative RT-PCR disclosed that VEGF-C mRNA copy numbers were higher than VEGF-D mRNA copy numbers in the rheumatoid arthritis (RA), osteoarthritis, and control patient groups studied (p < 0.01). Immunohistochemical staining localized VEGF-C to synovial lining cell layer, pericytes, and smooth muscle cells of blood vessels. The number of VEGF-C positive cells was increased in the synovial lining of ankylosing spondylitis (AS) and RA compared to control synovium. However, in contrast to control synovial lining, little if any VEGF-D was detected in AS or RA synovial lining. VEGFR-2 expressing stromal blood vessels, also positive for the vascular endothelial marker PAL-E and the basement membrane marker laminin, were more abundant in RA and AS than in controls. Interestingly, the lymphatic endothelial receptor VEGFR-3 was also expressed in most synovial vessels, especially in the sublining capillaries and venules. Conclusion. VEGF-C is strongly expressed in the hypertrophic synovial lining of arthritic joints, whereas VEGF-D expression is very low in AS and RA. The expression of VEGF-C and VEGF-D in pericytes and smooth muscle cells suggests that these factors may have a role in maintaining vascular homeostasis. The VEGF receptors VEGFR-2 and VEGFR-3 are present in most of the sublining blood vessels. The expression of the lymphatic marker VEGFR-3 in the sublining blood vessels may relate to fluid filtration and/or fenestrations. The relatively few lymphatic vessels along with increased vascular permeability in RA may contribute to the development of tissue edema and joint stiffness. (J Rheumatol 2002;29:39-45) Key Indexing Terms:
RHEUMATOID ARTHRITIS
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