Vascular endothelial growth factors C and D and their VEGFR-2 and 3 receptors in blood and lymphatic vessels in healthy and arthritic synovium.
OBJECTIVE
To localize vascular endothelial growth factor C (VEGF-C) and VEGF-D in synovial specimens in relation to their VEGFR-2 and VEGFR-3 receptors in blood and lymphatic vessels.


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.


CONCLUSIONS
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.
Paavonen
Karri
K
Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Finland.
Mandelin
Jami
J
Partanen
Taina
T
Jussila
Lotta
L
Li
Tian-Fang
TF
Ristimaki
Ari
A
Alitalo
Kari
K
Konttinen
Yrjö T
YT
D001168:Arthritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001808:Blood Vessels / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004727:Endothelium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000276:immunology / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3
D016207:Cytokines; D016228:Endothelial Growth Factors; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3