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

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.

SUBMITTER: Scheitlin CG

PROVIDER: S-EPMC4796279 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Scheitlin Christopher G CG Julian Justin A JA Shanmughapriya Santhanam S Madesh Muniswamy M Tsoukias Nikolaos M NM Alevriadou B Rita BR

American journal of physiology. Cell physiology 20160106 6

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 ...[more]

PMID: 26739489

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Project description:Blood flow produces mechanical frictional forces, parallel to the blood flow exerted on the endothelial wall of the vessel, the so-called wall shear stress (WSS). WSS sensing is associated with several vascular pathologies, but it is first a physiological phenomenon. Endothelial cell sensitivity to WSS is involved in several developmental and physiological vascular processes such as angiogenesis and vascular morphogenesis, vascular remodeling, and vascular tone. Local conditions of blood flow determine the characteristics of WSS, i.e., intensity, direction, pulsatility, sensed by the endothelial cells that, through their effect of the vascular network, impact WSS. All these processes generate a local-global retroactive loop that determines the ability of the vascular system to ensure the perfusion of the tissues. In order to account for the physiological role of WSS, the so-called shear stress set point theory has been proposed, according to which WSS sensing acts locally on vessel remodeling so that WSS is maintained close to a set point value, with local and distant effects of vascular blood flow. The aim of this article is (1) to review the existing literature on WSS sensing involvement on the behavior of endothelial cells and its short-term (vasoreactivity) and long-term (vascular morphogenesis and remodeling) effects on vascular functioning in physiological condition; (2) to present the various hypotheses about WSS sensors and analyze the conceptual background of these representations, in particular the concept of tensional prestress or biotensegrity; and (3) to analyze the relevance, explanatory value, and limitations of the WSS set point theory, that should be viewed as dynamical, and not algorithmic, processes, acting in a self-organized way. We conclude that this dynamic set point theory and the biotensegrity concept provide a relevant explanatory framework to analyze the physiological mechanisms of WSS sensing and their possible shift toward pathological situations.

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

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

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