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J. Biol. Chem., Vol. 280, Issue 14, 13349-13354, April 8, 2005

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Hypoxic Modulation of Ca²⁺ Signaling in Human Venous Endothelial Cells

MULTIPLE ROLES FOR REACTIVE OXYGEN SPECIES^*

Parvinder K. Aley, Karen E. Porter, John P. Boyle, Paul J. Kemp, and Chris Peers¶

From the School of Medicine, University of Leeds, Leeds LS2 9JT and School of Biosciences, University of Cardiff, Cardiff CF10 3US, United Kingdom

The effects of hypoxia (pO₂ 25 mm Hg) on Ca²⁺ signaling stimulated by extracellular ATP in human saphenous vein endothelial cells were investigated using fluorimetric recordings from Fura-2 loaded cells. In the absence of extracellular Ca²⁺, ATP-evoked rises of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) because of mobilization from the endoplasmic reticulum (ER). These responses were reduced by prior exposure to hypoxia but potentiated during hypoxia. Hypoxia itself liberated Ca²⁺ from the ER, but unlike the effects of ATP this effect was not inhibited by blockade of the inositol trisphosphate receptor. By contrast, ryanodine blocked the effects of hypoxia but not those of ATP. Antioxidants abolished the effects of hypoxia but potentiated the effects of ATP. Inhibition of NADPH oxidase also augmented ATP-evoked responses but was without effect on hypoxia-evoked rises of [Ca²⁺]_i. However, either uncoupling mitochondrial electron transport or inhibiting complex I markedly suppressed the actions of hypoxia yet exerted only small inhibitory effects on ATP-evoked rises of [Ca²⁺]_i. Both hypoxia and ATP were able to activate capacitative Ca²⁺ entry. Our results indicate that hypoxia regulates intracellular Ca²⁺ signaling via two distinct pathways. First, it modulates agonist-evoked liberation of Ca²⁺ from the ER primarily through regulation of reactive oxygen species generation from NADPH oxidase. Second, it liberates Ca²⁺ from the ER via ryanodine receptors, an effect requiring mitochondrial reactive oxygen species generation. These findings suggest that local O₂ tension is a major determinant of Ca²⁺ signaling in the vascular endothelium, a finding that is likely to be of both physiological and pathophysiological importance.

Received for publication, December 6, 2004

^* This work was supported by the British Heart Foundation, Medical Research Council, Wellcome Trust, and the Biotechnology and Biological Sciences Research Council/Pfizer Central Research (through a Collaborative Awards in Science and Engineering award to P. K. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: School of Medicine, University of Leeds, Leeds LS2 9JT, UK. Tel.: 113-343-4174; Fax: 113-343-4803; E-mail: c.s.peers{at}leeds.ac.uk.

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