Angiogenesis and blood vessel stability in inflammatory arthritis.
OBJECTIVE
To assess blood vessel stability in inflammatory synovial tissue (ST) and to examine neural cell adhesion molecule (NCAM), oxidative DNA damage, and hypoxia in vivo.


METHODS
Macroscopic vascularity and ST oxygen levels were determined in vivo in patients with inflammatory arthritis who were undergoing arthroscopy. Vessel maturity/stability was quantified in matched ST samples by dual immunofluorescence staining for factor VIII (FVIII)/alpha-smooth muscle actin (alpha-SMA). NCAM and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) were examined by immunohistochemistry. Angiogenesis was assessed in vitro, using human dermal endothelial cells (HDECs) in a Matrigel tube formation assay.


RESULTS
A significant number of immature vessels (showing no pericyte recruitment) was observed in tissue from patients with inflammatory arthritis (P < 0.001), in contrast to osteoarthritic and normal tissue, which showed complete recruitment of pericytes. Low in vivo PO(2) levels in the inflamed joint (median [range] 22.8 [3.2-54.1] mm Hg) were inversely related to increased macroscopic vascularity (P < 0.04) and increased microscopic expression of FVIII and alpha-SMA (P < 0.04 and P < 0.03, respectively). A significant proportion of vessels showed focal expression of NCAM and strong nuclear 8-oxodG expression, implicating a loss of EC-pericyte contact and increased DNA damage, levels of which were inversely associated with low in vivo PO(2) (P = 0.04 for each comparison). Circulating cells were completely negative for 8-oxodG. Exposure of HDEC to 3% O(2) (reflecting mean ST in vivo measurements) significantly increased EC tube formation (P < 0.05).


CONCLUSIONS
Our findings indicate the presence of unstable vessels in inflamed joints associated with hypoxia, incomplete EC-pericyte interactions, and increased DNA damage. These changes may further contribute to persistent hypoxia in the inflamed joint to further drive this unstable microenvironment.
Kennedy
Aisling
A
Dublin Academic Health Care, St. Vincent's University Hospital and The Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
Ng
Chin Teck
CT
Biniecka
Monika
M
Saber
Tajvur
T
Taylor
Cormac
C
O'Sullivan
Jacintha
J
Veale
Douglas J
DJ
Fearon
Ursula
U
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis / Q000473:pathology / Q000503:physiopathology*; D001808:Blood Vessels / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D019006:Neural Cell Adhesion Molecules / Q000032:analysis; D010100:Oxygen / Q000032:analysis; D013583:Synovial Membrane / Q000098:blood supply*
D019006:Neural Cell Adhesion Molecules; D010100:Oxygen