Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair

Bartolo Ferraro, Giovanna Leoni, Rabea Hinkel, Steffen Ormanns, Nicole Paulin, Almudena Ortega-Gomez, Joana R. Viola, Renske de Jong, Dario Bongiovanni, Tarik Bozoglu, Sanne L. Maas, Michele D'Amico, Thorsten Kessler, Tanja Zeller, Michael Hristov, Chris Reutelingsperger, Hendrik B. Sager, Yvonne Doering, Matthias Nahrendorf, Christian KupattOliver Soehnlein*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

82 Citations (Web of Science)


BACKGROUND Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration.

OBJECTIVES This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI.

METHODS AnxA1 knockout (AnxA1(-/-)) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1.

RESULTS AnxA1(-/-) mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1(-/-) mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx(3)cr1cre(ERT2)Vegf(flox/flox) or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus.

CONCLUSIONS AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Original languageEnglish
Pages (from-to)2990-3002
Number of pages13
JournalJournal of the American College of Cardiology
Issue number23
Publication statusPublished - 18 Jun 2019


  • annexin A1
  • cardiac repair
  • inflammation
  • myocardial infarct
  • neovascularization

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