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 Döring
  • Matthias Nahrendorf
  • Christian Kupatt
  • Oliver Soehnlein

Abstract

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 Cx3cr1creERT2Vegfflox/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.

Bibliographical metadata

Original languageEnglish
ISSN0735-1097
DOIs
Publication statusPublished - 18.06.2019
PubMed 31196457