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Flow pattern–dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells
Soon-Gook Hong, … , Xiaofeng Yang, Joon-Young Park
Soon-Gook Hong, … , Xiaofeng Yang, Joon-Young Park
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(18):e159286. https://doi.org/10.1172/jci.insight.159286.
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Research Article Vascular biology

Flow pattern–dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells

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Abstract

Endothelial mitochondria play a pivotal role in maintaining endothelial cell (EC) homeostasis through constantly altering their size, shape, and intracellular localization. Studies show that the disruption of the basal mitochondrial network in EC, forming excess fragmented mitochondria, implicates cardiovascular disease. However, cellular consequences underlying the morphological changes in the endothelial mitochondria under distinctively different, but physiologically occurring, flow patterns (i.e., unidirectional flow [UF] versus disturbed flow [DF]) are largely unknown. The purpose of this study was to investigate the effect of different flow patterns on mitochondrial morphology and its implications in EC phenotypes. We show that mitochondrial fragmentation is increased at DF-exposed vessel regions, where elongated mitochondria are predominant in the endothelium of UF-exposed regions. DF increased dynamin-related protein 1 (Drp1), mitochondrial reactive oxygen species (mtROS), hypoxia-inducible factor 1, glycolysis, and EC activation. Inhibition of Drp1 significantly attenuated these phenotypes. Carotid artery ligation and microfluidics experiments further validate that the significant induction of mitochondrial fragmentation was associated with EC activation in a Drp1-dependent manner. Contrarily, UF in vitro or voluntary exercise in vivo significantly decreased mitochondrial fragmentation and enhanced fatty acid uptake and OXPHOS. Our data suggest that flow patterns profoundly change mitochondrial fusion/fission events, and this change contributes to the determination of proinflammatory and metabolic states of ECs.

Authors

Soon-Gook Hong, Junchul Shin, Soo Young Choi, Jeffery C. Powers, Benjamin M. Meister, Jacqueline Sayoc, Jun Seok Son, Ryan Tierney, Fabio A. Recchia, Michael D. Brown, Xiaofeng Yang, Joon-Young Park

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Figure 1

Excessive mitochondrial fragmentation in DF-exposed vessel regions instigates atheroprone endothelial phenotypes in vivo.

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Excessive mitochondrial fragmentation in DF-exposed vessel regions insti...
(A) A strategy to generate EC-PhAM mouse (left). In the bracket (right), en face staining, frozen cryosection of aortic ring, phase contrast micrograph of mouse aortic endothelial cells from EC-PhAM mice (MAECEC-PhAM), epifluorescence image of MAECEC-PhAM, en face lesser curvature, and en face thoracic aorta are shown. Mitochondria (green), VE-Cadherin (red), and DAPI (blue) are shown. Scale bar: 200 μm (63× oil lens, phase contrast; middle left) and 20 μm (all others). (B) Representative micrographs of mitochondrial morphology at various vessel regions of the arteries. Scale bar: 20 μm. (C) Mitochondrial fission count (MFC, mitochondria number/total mitochondria area) (n = 8). **P < 0.01. (D–G) Representative images and plots of each total Drp1 (D), dephospho-Drp1 Ser637 (E), DHE (F), and VCAM-1 (G) in the endothelium of lesser curvature (LC, a DF region) and thoracic aorta (TA, a UF region). Scale bar: 20 μm (n = 5–7; 63× objective lens). Data are shown as mean ± SD; **P < 0.01 by 1-way ANOVA and Tukey’s post hoc tests (C); 2-tailed independent Student’s t test (D, F, and G); and Mann-Whitney U test (E). A.U., arbitrary unit.

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