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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 2

Flow pattern instantaneously but reversibly alters mitochondrial morphology in a Drp1-dependent fashion in primary mouse aortic endothelial cells.

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Flow pattern instantaneously but reversibly alters mitochondrial morphol...
(A) Mitochondrial morphology classification based on aspect ratio (AR) and form factor (FF). The endothelial mitochondria morphology was classified into 3 subgroups (fragmented, tubular, or elongated) based on AR and FF. (B) Quantification plots of mitochondrial morphology under DF versus UF. Primary cultured aortic endothelial cells from EC-PhAM mice (MAECPhAM) were used. (C) Representative immunoblot images for the protein expression of phospho-Drp1 at Ser637. α-Tubulin was used as a loading control. Quantification plots of phospho-Drp1 at Ser637 under UF versus DF (n = 5). (D) Micrographs of endothelial mitochondria under UF and 3 hours after flow transition from UF to DF (n = 4). Scale bar: 20 μm. (E–H) Quantification plots of mitochondrial morphology analyses (AR, FF, and branch length [BL]) under UF and 3 hours after the flow transition from UF to DF. MFC was calculated as number of particles/total area of mitochondria (n = 4–6). (I) Ultrastructure of mitochondria in HUVECs under UF versus DF. Two sets of representative images are shown. HUVECs were transfected with either scrambled or Drp1 siRNA and subjected to either UF (20 dyne/cm2) or DF (5 dyne/cm2, 1 Hz) for 48 hours (transition electron microscopy [TEM], 50,000×). Scale bar: 400 nm (n = 3). Data are shown as mean ± SD. *P < 0.05, **P < 0.01. by 2-tailed independent Student’s t test (C and G) or Welch’s t test (E, F, and H). A.U., arbitrary unit; UF, unidirectional flow; DF, disturbed flow.

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