Endothelial Dysfunction in Rheumatoid Arthritis: Mechanistic Insights and Correlation with Circulating Markers of Systemic Inflammation

PLoS One. 2016 Jan 13;11(1):e0146744. doi: 10.1371/journal.pone.0146744. eCollection 2016.


Objectives: To determine mechanisms involved in endothelial dysfunction (ED) during the course of arthritis and to investigate the link between cytokines, chemokines and osteoprotegerin.

Approach and results: Experiments were conducted on aortic rings at day 4 (preclinical), day 11 (onset of disease), day 33 (acute disease) and day 90 (chronic disease) after adjuvant-induced arthritis (AIA) in Lewis rats. At day 4, the unique vascular abnormality was a reduced norepinephrine-induced constriction. At day 11, endothelial function assessed by the relaxation to acetylcholine was normal despite increased cyclo-oxygenase-2 activity (COX-2) and overproduction of superoxide anions that was compensated by increased nitric oxide synthase (NOS) activity. At day 33, ED apparition coincides with the normalization of NOS activity. At day 90, ED was only observed in rats with a persisting imbalance between endothelial NOS and COX-2 pathways and higher plasma levels of IL-1β and TNFα. Plasma levels of IL-1β, TNFα and MIP-1α negatively correlated with Ach-induced relaxation throughout the course of AIA.

Conclusions: Our data identified increased endothelial NOS activity as an important compensatory response that opposes the ED in the early arthritis. Thereafter, a cross-talk between endothelial COX-2/NOS pathways appears as an important element for the occurrence of ED. Our results encourage determining the clinical value of IL-1β, TNFα and MIP-1α as biomarkers of ED in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Arthritis, Experimental / blood
  • Arthritis, Experimental / diagnostic imaging
  • Arthritis, Experimental / physiopathology
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / diagnostic imaging
  • Arthritis, Rheumatoid / physiopathology*
  • Biomarkers / blood*
  • Chemokines / blood
  • Cyclic N-Oxides / pharmacology
  • Cyclooxygenase 2 / metabolism
  • Disease Progression
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology*
  • Immunization
  • Inflammation / blood*
  • Inflammation / complications
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrobenzenes / pharmacology
  • Nitroprusside / pharmacology
  • Osteoprotegerin / blood
  • Radiography
  • Rats, Inbred Lew
  • Spin Labels
  • Sulfonamides / pharmacology
  • Superoxides / metabolism
  • Time Factors
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects


  • Biomarkers
  • Chemokines
  • Cyclic N-Oxides
  • Nitrobenzenes
  • Osteoprotegerin
  • Spin Labels
  • Sulfonamides
  • Superoxides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Nitroprusside
  • Nitric Oxide Synthase Type III
  • Cyclooxygenase 2
  • Acetylcholine
  • tempol
  • NG-Nitroarginine Methyl Ester

Grant support

This work was supported by funding from the French Ministry for Higher Education and Research of Totoson Thesis project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.