Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia

Gustavo Falero-Diaz, Catarina A. de Barboza, Felipe Pires, Maeva Fanchin, Jingjing Ling, Zachary M. Zigmond, Anthony J. Griswold, Laisel Martinez, Roberto I. Vazquez-Padron, Omaida C. Velazquez, Roberta M. Lassance-Soares

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

OBJECTIVE: Monocytes, which play an important role in arteriogenesis, can build immunologic memory by a functional reprogramming that modifies their response to a second challenge. This process, called trained immunity, is evoked by insults that shift monocyte metabolism, increasing HIF (hypoxia-inducible factor)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. METHODS AND RESULTS: Mice exposed to ischemia by 24 hours (24h) of femoral artery occlusion (24h trained) or sham were subjected to hindlimb ischemia one week later; the 24h trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24h trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24h ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 (glucose transporter-1) gene expression during femoral artery occlusion. Circulating cytokines and GLUT-1 were also upregulated during femoral artery occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24h trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, 4 were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24h hypoxia. CONCLUSIONS: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.

Original languageEnglish (US)
Pages (from-to)175-188
Number of pages14
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume42
Issue number2
DOIs
StatePublished - Feb 1 2022
Externally publishedYes

Keywords

  • Bone marrow
  • Hindlimb
  • Ischemia
  • Lipids
  • Monocytes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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