Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with ¹⁸F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood.

Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E–deficient (ApoE^−/−) mouse model of atherosclerosis.

We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE^−/− mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE^−/− hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1α signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common β subunit of the granulocyte-macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1^+/−, ApoE^−/−, and ApoE^−/−Glut1^+/− mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE^−/− hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE^−/− mice transplanted with ApoE^−/− bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice.

We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE^−/− mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis.