MAb therapy against the IFN-alpha/beta receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden

Paul F. A. Teunissen, Marieke C. Boshuizen, Maurits R. Hollander, Paul. S. Biesbroek, Nina W. van der Hoeven, Jan-Quinten Mol, Marion J. Gijbels, Saskia van der Velden, Tineke C. van der Pouw Kraan, Anton J. Horrevoets, Menno P. de Winther*, Niels van Royen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


IFN-beta (IFN?) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFN? hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFN? treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFN? signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis.In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-?/? receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFN? were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice.Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.Published on behalf of the European Society of Cardiology. All rights reserved. ? The Author 2015. For permissions please email:
Original languageEnglish
Pages (from-to)255-266
JournalCardiovascular Research
Issue number2
Publication statusPublished - 15 Jul 2015


  • Collateral circulation
  • Atherosclerosis
  • MAbs
  • Animal model cardiovascular disease
  • Cytokine

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