© 2000 American Heart Association, Inc.
Integrative Physiology |
Antiangiogenic Effect of Interleukin-10 in Ischemia-Induced Angiogenesis in Mice Hindlimb
From INSERM U541, Hôpital Lariboisière, Institut Fédératif de Recherche "Circulation, Paris 7" (J.S.S., Z.M., M.D., R.T., A.T., B.I.L.), Paris; Unité Mixte de Recherche 7001, Centre National de la Recherche Scientifique/ENSCP/Aventis, Aventis Gencell (M.F.B., D.S.), Vitry; and Aventis Gencell (N.D., D.B.), Vitry, France.
Correspondence to Bernard I. Levy, U541-INSERM, Hôpital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris cedex 10, France. E-mail levy{at}infobiogen.fr
Abstract—Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)–10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-10+/+ and IL-10–/– mice. After 28 days, angiogenesis was quantified by microangiography, capillary, and arteriole density measurement and laser Doppler perfusion imaging. The protein levels of IL-10 and vascular endothelial growth factor (VEGF) were determined by Western blot analysis in hindlimbs. IL-10 was markedly expressed in the ischemic hindlimb of IL-10+/+ mice. Angiogenesis in the ischemic hindlimb was significantly increased in IL-10–/– compared with IL-10+/+ mice. Indeed, angiographic data showed that vessel density in the ischemic leg was 10.2±0.1% and 5.7±0.4% in IL-10–/– and IL-10+/+ mice, respectively (P<0.01). This corresponded to improved ischemic/nonischemic leg perfusion ratio by 1.4-fold in IL-10–/– mice compared with IL-10+/+ mice (0.87±0.05 versus 0.63±0.01, respectively; P<0.01). Revascularization was associated with a 1.8-fold increase in tissue VEGF protein level in IL-10–/– mice compared with IL-10+/+ mice (P<0.01). In vivo electrotransfer of murine IL-10 cDNA in IL-10–/– mice significantly inhibited both the angiogenic process and the rise in VEGF protein level observed in IL-10–/– mice. No changes in vessel density or VEGF content were observed in the nonischemic hindlimb. These findings underscore the antiangiogenic effect of IL-10 associated with the downregulation of VEGF expression and suggest a role for the inflammatory balance in the modulation of ischemia-induced angiogenesis.
Key Words: angiogenesis • ischemia • inflammation • interleukin-10
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