Angiogenesis and blood vessel stability in inflammatory arthritis

Arthritis Rheum. 2010 Mar;62(3):711-21. doi: 10.1002/art.27287.

Abstract

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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis / pathology
  • Arthritis / physiopathology*
  • Blood Vessels / physiopathology*
  • Cell Hypoxia / physiology
  • DNA Damage / physiology
  • Humans
  • Immunohistochemistry
  • Inflammation
  • Middle Aged
  • Neovascularization, Pathologic
  • Neural Cell Adhesion Molecules / analysis
  • Oxygen / analysis
  • Synovial Membrane / blood supply*

Substances

  • Neural Cell Adhesion Molecules
  • Oxygen