Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: Role of the Na+-glucose cotransporter

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Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca2+]i) which then activates the phospholipase A2 (PLA2). The link between the decrease in ATP and the increase in [Ca2+]i was not known and is investigated in this work. We first showed that the presence of extracellular Na+ was necessary to observe the hypoxia-induced increase in [Ca2+]i and the activation of PLA2. This increase was not due to the release of Ca2+ from intracellular stores, since thapsigargin did not inhibit this process. The Na+/Ca2+ exchanger was involved since dichlorobenzamil inhibited the [Ca2+]i and the PLA2 activation. The glycolysis was activated, but the intracellular pH (pHi) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca2+]i and PLA2 activation were inhibited by phlorizin, an inhibitor of the Na+-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na+ through the activated Na+-glucose cotransport followed by the activation of the Na+/Ca2+ exchanger, resulting in a net influx of Ca2+. © 2001 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)115-131
Number of pages17
JournalJournal of cellular biochemistry
Issue number1
Publication statusPublished - 2001


  • Endothelial cells
  • Hypoxia
  • Intracellular calcium concentration
  • Na-glucose transporter
  • Na/Ca exchanger


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