Ischemic-trained monocytes improve arteriogenesis in a mouse model of hindlimb ischemia.

Roberta M. Lassance-Soares

Objective: Monocytes, which play an important role in arteriogenesis, can build immunological 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 hypoxia-inducible factor (HIF)-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 24h of femoral artery (FA) 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. Monocyte 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 gene expression during 24h of FA occlusion, which returned to baseline values 2 days after the opening of the FA (when ischemia was ended and monocytes isolated for the experiments – 24h trained group). Transcriptomic analysis and confirmatory qPCR performed in 24h trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, four were involved in lipid metabolism in the ischemic-trained monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24h hypoxia.
Conclusion: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.


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