Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm

Anantha Vijay R. Santhanam, Leslie A. Smith, Masahiko Akiyama, A. Gabriela Rosales, Kent R. Bailey, Zvonimir S. Katusic

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Background and Purpose - In the present study, the effect of subarachnoid hemorrhage (SAH) on the phosphorylation of endothelial NO synthase (eNOS) and the ability of recombinant erythropoietin (Epo) to augment this vasodilator mechanism in the spastic arteries were studied. Methods - Recombinant adenoviral vectors (109 plaque-forming units per animal) encoding genes for human Epo (AdEpo), and β-galactosidase were injected immediately after injection of autologous arterial blood into the cisterna magna (day 0) of rabbits. Cerebral angiography was performed on day 0 and day 2, and basilar arteries were harvested for Western blots, measurement of cGMP levels, and analysis of vasomotor functions. Results - Injection of autologous arterial blood into cisterna magna resulted in significant vasospasm of the basilar arteries. Despite the narrowing of arterial diameter and reduced expression of eNOS, expressions of phosphorylated protein kinase B (Akt) and phosphorylated eNOS were significantly increased in spastic arteries. Gene transfer of AdEpo reversed the vasospasm. AdEpo-transduced basilar arteries demonstrated significant augmentation of the endothelium-dependent relaxations to acetylcholine, whereas the relaxations to an NO donor, 2-(N,N-diethylamino) diazenolate-2-oxide sodium salt, were not affected. Transduction with AdEpo further increased the expression of phosphorylated Akt and eNOS and elevated basal levels of cGMP in the spastic arteries. Conclusions - Phosphorylation of eNOS appears to be an adaptive mechanism activated during development of vasospasm. The vascular protective effect of Epo against cerebral vasospasm induced by SAH may be mediated in part by phosphorylation of Akt/eNOS.

Original languageEnglish (US)
Pages (from-to)2731-2737
Number of pages7
JournalStroke
Volume36
Issue number12
DOIs
StatePublished - Dec 2005

Keywords

  • Basilar artery
  • Gene therapy
  • Nitric oxide

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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