Published Online
on November 3, 2005

A more recent version of this article appeared on December 1, 2005

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Submitted on June 1, 2005
Revised on September 6, 2005
Accepted on September 23, 2005

Role of Endothelial NO Synthase Phosphorylation in Cerebrovascular Protective Effect of Recombinant Erythropoietin During Subarachnoid Hemorrhage- Induced Cerebral Vasospasm

Anantha Vijay R. Santhanam PhD; Leslie A. Smith; Masahiko Akiyama MD; A. Gabriela Rosales MS; Kent R. Bailey PhD; and Zvonimir S. Katusic MD, PhD^*

From the Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics (A.V.R.S., L.A.S., M.A., Z.S.K.), Division of Biostatistics (A.G.R., K.R.B.), Mayo Clinic College of Medicine, Rochester, Minn.

^* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.

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 -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.

Key words: basilar artery • gene therapy • nitric oxide

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