Endothelial cell respiration is affected by the oxygen tension during shear exposure: role of mitochondrial peroxynitrite

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Abstract
Cultured vascular endothelial cell (EC) exposure to steady laminar shear stress results in peroxynitrite (ONOO−) formation intramitochondrially and inactivation of the electron transport chain. We examined whether the “hyperoxic state” of 21% O2, compared with more physiological O2 tensions (Po2), increases the shear-induced nitric oxide (NO) synthesis and mitochondrial superoxide (O2·−) generation leading to ONOO− formation and suppression of respiration. Electron paramagnetic resonance oximetry was used to measure O2 consumption rates of bovine aortic ECs sheared (10 dyn/cm2, 30 min) at 5%, 10%, or 21% O2 or left static at 5% or 21% O2. Respiration was inhibited to a greater extent when ECs were sheared at 21% O2 than at lower Po2 or left static at different Po2. Flow in the presence of an endothelial NO synthase (eNOS) inhibitor or a ONOO− scavenger abolished the inhibitory effect. EC transfection with an adenovirus that expresses manganese superoxide dismutase in mitochondria, and not a control virus, blocked the inhibitory effect. Intracellular and mitochondrial O2·− production was higher in ECs sheared at 21% than at 5% O2, as determined by dihydroethidium and MitoSOX red fluorescence, respectively, and the latter was, at least in part, NO-dependent. Accumulation of NO metabolites in media of ECs sheared at 21% O2 was modestly increased compared with ECs sheared at lower Po2, suggesting that eNOS activity may be higher at 21% O2. Hence, the hyperoxia of in vitro EC flow studies, via increased NO and mitochondrial O2·− production, leads to enhanced ONOO− formation intramitochondrially and suppression of respiration.

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