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Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis
Christelle Guillermier, … , Matthew L. Steinhauser, Jonathan D. Brown
Christelle Guillermier, … , Matthew L. Steinhauser, Jonathan D. Brown
Published June 6, 2019
Citation Information: JCI Insight. 2019;4(11):e128528. https://doi.org/10.1172/jci.insight.128528.
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Resource and Technical Advance Vascular biology

Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis

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Abstract

Atherosclerotic plaques feature local proliferation of leukocytes and vascular smooth muscle cells (VSMCs) and changes in cellular metabolism. Yet the relationship between glucose utilization and proliferation has been technically impossible to study directly in cells of atherosclerotic plaques in vivo. We used multi-isotope imaging mass spectrometry (MIMS), a quantitative imaging platform, to measure coincident cell division and glucose utilization at suborganelle resolution in atherosclerotic plaques. In established plaques, 65% of intimal foam cells and only 4% of medial VSMCs were labeled with 15N-thymidine after 1 week of isotope treatment. Dividing cells demonstrated heightened glucose labeling. MIMS detected 2H-glucose label in multiple subcellular compartments within foam cells, including lipid droplets, the cytosol, and chromatin. Unexpectedly, we identified an intensely focal region of 2H-label in VSMCs underlying plaques. This signal diminished in regions of aorta without atherosclerosis. In advanced plaques, 15N-thymidine and 2H-glucose labeling in foam cells and VSMCs significantly decreased. These data demonstrate marked heterogeneity in VSMC glucose metabolism that was dependent on both proliferative status and proximity of VSMCs to plaques. Furthermore, these results reveal how quantitative mass spectrometry coupled with isotope imaging can complement other methods used to study cell biology directly in the growing atherosclerotic plaque in vivo.

Authors

Christelle Guillermier, Sean P. Doherty, Adam G. Whitney, Vladimir R. Babaev, MacRae F. Linton, Matthew L. Steinhauser, Jonathan D. Brown

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Figure 4

Cell proliferation and glucose metabolism decrease in advanced atherosclerotic plaques.

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Cell proliferation and glucose metabolism decrease in advanced atheroscl...
(A) Intimal 2H-glucose labeling in advanced plaques (atherogenic diet for 22 weeks). Each dot denotes an individual cell. Data was pooled from n = 3 mice. Bars denote median ± interquartile range. Significance was assessed by Mann-Whitney U test. (B) 2H-glucose labeling in foam cells versus VSMCs of advanced atherosclerotic plaques (atherogenic diet for 22 weeks). Each dot denotes an individual cell. Data were pooled from n = 3 mice. Bars denote median ± interquartile range. Significance was assessed by nonparametric ANOVA and Kruskal-Wallis test. (C) Frequency of proliferation (%15N-labeled) by cell type in established versus advanced atherosclerosis. Each dot represents the average frequency in 1 mouse (n = 3 mice per time point). Significance was assessed by 2-sided t test.

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