Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice

Thomas L. Theelen, Jari P. Lappalainen, Judith C. Sluimer, Erika Gurzeler, Jack P. Cleutjens, Marion J. Gijbels, Erik A. L. Biessen, Mat J. A. P. Daemen, Kari Alitalo, Seppo Yla-Herttuala*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B-100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8. To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p <0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p <0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice.
Original languageEnglish
Pages (from-to)297-304
JournalAtherosclerosis
Volume241
Issue number2
DOIs
Publication statusPublished - Aug 2015

Keywords

  • Angiogenesis
  • Microvascular leakage
  • Plaque stability
  • Angiopoietin-2
  • Atherosclerosis

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