Endothelin-1 protects astrocytes from hypoxic/ischemic injury

FASEB J. 2001 Mar;15(3):618-26. doi: 10.1096/fj.99-1022com.


Under pathological conditions such as ischemia (I), subarachnoid hemorrhage, and Alzheimer's disease, astrocytes show a large increase in endothelin (ET) -like immunoreactivity. However, it is not clear whether ET is protective or destructive to these cells during brain injury. Using astrocytes from ET-1-deficient mice, we determined the effect of ET-1 on these cells under normal, hypoxic (H), and hypoxic/ischemic (H/I) conditions. Under normal culture conditions, astrocytes from wild-type and ET-1-deficient mice showed no difference in their morphology and cell proliferation rates. ET-3 and ETA receptor mRNAs were up-regulated whereas ETB receptor mRNA was down-regulated in ET-1-deficient astrocytes, suggesting that ET-1 and ET-3 may complement each other's functions and that the expressions of these endothelins and their receptors are regulated by a complex feedback mechanism. Under H and H/I conditions, ET-1 peptide and mRNA were up-regulated in wild-type astrocytes, and the astrocytes without ET-1 died faster than the wild-type astrocytes, as indicated by greater efflux of lactate dehydrogenase. The present study suggests that astrocytes without ET-1 are more vulnerable to H and H/I injuries and that the up-regulation of astrocytic ET-1 is essential for the survival of astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / physiology*
  • Blotting, Western
  • Brain Chemistry
  • Cell Division
  • Cell Hypoxia
  • Cell Size
  • Cells, Cultured
  • Culture Media, Serum-Free
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism*
  • Endothelin-1 / pharmacology
  • Endothelin-3 / genetics
  • Endothelin-3 / metabolism
  • Female
  • Gene Expression Regulation
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neuroprotective Agents
  • RNA, Messenger / metabolism
  • Receptors, Endothelin / genetics
  • Receptors, Endothelin / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Culture Media, Serum-Free
  • Endothelin-1
  • Endothelin-3
  • Glial Fibrillary Acidic Protein
  • Neuroprotective Agents
  • RNA, Messenger
  • Receptors, Endothelin
  • L-Lactate Dehydrogenase