Protective effects of macrophage-specific integrin 5 in myocardial infarction are associated with accentuated angiogenesis

Macrophages sense changes in the extracellular matrix environment through the integrins and play a central role in regulation of the reparative response after myocardial infarction. Here we show that macrophage integrin alpha 5 protects the infarcted heart from adverse remodeling and that the protective actions are associated with acquisition of an angiogenic macrophage phenotype. We demonstrate that myeloid cell- and macrophage-specific integrin alpha 5 knockout mice have accentuated adverse post-infarction remodeling, accompanied by reduced angiogenesis in the infarct and border zone. Single cell RNA-sequencing identifies an angiogenic infarct macrophage population with high Itga5 expression. The angiogenic effects of integrin alpha 5 in macrophages involve upregulation of Vascular Endothelial Growth Factor A. RNA-sequencing of the macrophage transcriptome in vivo and in vitro followed by bioinformatic analysis identifies several intracellular kinases as potential downstream targets of integrin alpha 5. Neutralization assays demonstrate that the angiogenic actions of integrin alpha 5-stimulated macrophages involve activation of Focal Adhesion Kinase and Phosphoinositide 3 Kinase cascades. During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin alpha 5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.