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Am J Physiol Cell Physiol. 2016 Mar 15;310(6):C479-90. doi: 10.1152/ajpcell.00171.2015. Epub 2016 Jan 6.

Endothelial mitochondria regulate the intracellular Ca2+ response to fluid shear stress.

Author information

1
Departments of Biomedical Engineering and Internal Medicine, Division of Cardiovascular Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio;
2
Department of Medical Genetics and Molecular Biochemistry and Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania; and.
3
Department of Biomedical Engineering, Florida International University, Miami, Florida.
4
Departments of Biomedical Engineering and Internal Medicine, Division of Cardiovascular Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; rita.alevriadou@osumc.edu alevriadou.1@osu.edu.

Abstract

Shear stress is known to stimulate an intracellular free calcium concentration ([Ca(2+)]i) response in vascular endothelial cells (ECs). [Ca(2+)]i is a key second messenger for signaling that leads to vasodilation and EC survival. Although it is accepted that the shear-induced [Ca(2+)]i response is, in part, due to Ca(2+) release from the endoplasmic reticulum (ER), the role of mitochondria (second largest Ca(2+) store) is unknown. We hypothesized that the mitochondria play a role in regulating [Ca(2+)]i in sheared ECs. Cultured ECs, loaded with a Ca(2+)-sensitive fluorophore, were exposed to physiological levels of shear stress. Shear stress elicited [Ca(2+)]i transients in a percentage of cells with a fraction of them displaying oscillations. Peak magnitudes, percentage of oscillating ECs, and oscillation frequencies depended on the shear level. [Ca(2+)]i transients/oscillations were present when experiments were conducted in Ca(2+)-free solution (plus lanthanum) but absent when ECs were treated with a phospholipase C inhibitor, suggesting that the ER inositol 1,4,5-trisphosphate receptor is responsible for the [Ca(2+)]i response. Either a mitochondrial uncoupler or an electron transport chain inhibitor, but not a mitochondrial ATP synthase inhibitor, prevented the occurrence of transients and especially inhibited the oscillations. Knockdown of the mitochondrial Ca(2+) uniporter also inhibited the shear-induced [Ca(2+)]i transients/oscillations compared with controls. Hence, EC mitochondria, through Ca(2+) uptake/release, regulate the temporal profile of shear-induced ER Ca(2+) release. [Ca(2+)]i oscillation frequencies detected were within the range for activation of mechanoresponsive kinases and transcription factors, suggesting that dysfunctional EC mitochondria may contribute to cardiovascular disease by deregulating the shear-induced [Ca(2+)]i response.

KEYWORDS:

calcium oscillations; endothelial cell; fluid shear stress; intracellular calcium; mitochondria

PMID:
26739489
PMCID:
PMC4796279
DOI:
10.1152/ajpcell.00171.2015
[Indexed for MEDLINE]
Free PMC Article

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