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This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/H1497    most recent 00959.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Grundmann, S. Articles by Buschmann, I. Search for Related Content PubMed PubMed Citation Articles by Grundmann, S. Articles by Buschmann, I.

Anti-tumor necrosis factor- therapies attenuate adaptive arteriogenesis in the rabbit

¹Department for Internal Medicine III (Cardiology and Angiology), University Hospital Freiburg, Freiburg, Germany; ²Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam; ³Department of Experimental Cardiology, University Medical Center, Utrecht, The Netherlands; and ⁴University of Florida College of Medicine, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida

Submitted 14 September 2004 ; accepted in final form 19 May 2005

The specific antagonists of tumor necrosis factor- (TNF-), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn’s disease. Although the importance of TNF- in chronic inflammatory diseases is well established, little is known about its implications in the cardiovascular system. Because proliferation of arteriolar connections toward functional collateral arteries (arteriogenesis) is an inflammatory-like process, we tested in vivo the hypothesis that infliximab and etanercept have antiarteriogenic actions. Sixty-three New Zealand White rabbits underwent femoral artery occlusion and received infliximab, etanercept, or vehicle according to clinical dosage regimes. After 1 wk, collateral conductance, assessed with fluorescent microspheres, revealed significant inhibition of arteriogenesis (collateral conductance): 52.4 (SD 8.1), 35.2 (SD 7.7), and 33.3 (SD 10.1) ml·min^–1·100 mmHg^–1 with PBS, infliximab, and etanercept, respectively (P < 0.001). High-resolution angiography showed no significant differences in number of collateral arteries, but immunohistochemical analysis demonstrated a decrease in mean collateral diameter, proliferation of vascular smooth muscle cells, and reduction of leukocyte accumulation around collateral arteries in treated groups. Infliximab and etanercept bound to infiltrating leukocytes, which are important mediators of arteriogenesis. Infliximab induced monocyte apoptosis, and neither substance affected monocyte expression of the adhesion molecule Mac-1. We demonstrated that TNF- serves as a pivotal modulator of arteriogenesis, which is attenuated by treatment with TNF- inhibitors. Reduction of collateral conductance is most likely due to inhibition of perivascular leukocyte infiltration and subsequent lower vascular smooth muscle cell proliferation. This is the first report showing a negative influence of TNF- inhibitors on collateral artery growth.

collateral circulation; growth factors

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