Abstract MP225: Macrophage-specificα5 Integrin Signaling Protects The Infarcted Heart From Adverse Remodeling By Stimulating The Angiogenic Response

Abstract

Abundant macrophages infiltrate the infarcted heart and play a critical role in repair, remodeling and fibrosis. Macrophages sense changes in the extracellular matrix (ECM) environment through Integrins, thus activating signaling pathways that regulate their function. Analysis of our RNA sequencing data identified integrin α5 (Itgα5) as one of the most upregulated integrin genes in infarct macrophages. Accordingly, we hypothesized that integrin α5 signaling in infarct macrophages transduces ECM-derived signals, regulating responses critical for repair and remodeling of the infarcted heart.In order to study the role of macrophage α5 integrin in the infarcted heart, we generated 2 lines of macrophage-specific α5 integrin KO mice: myeloid cell-specific KOs (Myα5KO, using the lysozyme-M Cre driver) and inducible macrophage-specific α5 KOs (iMaα5KO, using CX3CR1 CreER ). 28 days after infarction, Myα5KO mice had accentuated adverse remodeling, evidenced by increased LVEDV and LVESV, a trend towards reduced ejection fraction. Adverse remodeling in Mya5KO was associated with a marked reduction in microvascular density in the infarct and in the border zone. iMaα5KO mice also exhibited worse remodeling and impaired infarct angiogenesis. A PCR array in infarct macrophages showed that α5 integrin loss was associated with markedly reduced transcription of VEGF-A, and lower levels of the angiogenic CXC chemokines CXCL1 and CXCL2. RNAseq followed by bioinformatic analysis predicted that that Nrf2, Erk5, HIF1a, p38 MAPK, VEGF, RhoA, and PI3K/Akt pathways were inhibited in the absence of α5 signaling in vivo (in infarct macrophages) and in vitro (in bone marrow macrophages undergoing α5 antibody neutralization experiments).In conclusion, α5 integrin promotes an angiogenic VEGF-expressing phenotype in infarct macrophages, protecting the infarcted heart from adverse remodeling. The angiogenic effects of α5 integrin in macrophages may have important therapeutic implications for heart failure patients.