Ischemic factor-induced increases in cerebral microvascular endothelial cell Na/H exchange activity and abundance: Evidence for involvement of ERK1/2 MAP kinase

Natalie Yuen, Tina I. Lam, Breanna K. Wallace, Nicholas R. Klug, Steven E. Anderson, Martha E O'Donnell

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24 Scopus citations


Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl, and water into the brain across an intact blood-brain barrier (BBB, together with swelling of astrocytes as they take up the ions and water crossing the BBB. Our previous studies provide evidence that luminal BBB Na-K-Cl cotransport (NKCC and Na/H exchange (NHE participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC are rapidly stimulated by the ischemic factors hypoxia, aglycemia, and AVP, and inhibition of NKCC and NHE activities by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. We examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundance. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemic factors. We found that hypoxia, aglycemia, and AVP increase CMEC NHE activity through 5 h and that NHE1, but not NHE2, abundance is increased by 1- to 5-h exposures to these factors. Furthermore, we found that these factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Issue number10
StatePublished - May 15 2014



  • Blood-brain barrier
  • Cerebral edema
  • ERK1/2 MAP kinase
  • FR180204
  • HOE642
  • Stroke

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

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