Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage

Document Type

Article

Abstract

We studied whether endothelial nitric oxide synthase (eNOS) is upregulated and uncoupled in large cerebral arteries after subarachnoid hemorrhage (SAH) and also whether this causes cerebral vasospasm in a mouse model of anterior circulation SAH. Control animals underwent injection of saline instead of blood (n16 SAH and n16 controls). There was significant vasospasm of the middle cerebral artery 2 days after SAH (lumen radius/wall thickness ratio 4.3±1.3 for SAH, 23.2±2.1 for saline, P0.001). Subarachnoid hemorrhage was associated with terminal deoxynucleotidyl transferase dUTP nick-end labeling, cleaved caspase-3, and Fluoro-Jade-positive neurons in the cortex and with CA1 and dentate regions in the hippocampus. There were multiple fibrinogen-positive microthromboemboli in the cortex and hippocampus after SAH. Transgenic mice expressing lacZ under control of the eNOS promoter had increased X-gal staining in large arteries after SAH, and this was confirmed by the increased eNOS protein on western blotting. Evidence that eNOS was uncoupled was found in that nitric oxide availability was decreased, and superoxide and peroxynitrite concentrations were increased in the brains of mice with SAH. This study suggests that artery constriction by SAH upregulates eNOS but that it is uncoupled and produces peroxynitrite that may generate microemboli that travel distally and contribute to brain injury. © 2011 ISCBFM All rights reserved.

Keywords

nitric oxide synthase, subarachnoid hemorrhage, vasospasm

Publication Date

1-1-2011

Publication Title

Journal of Cerebral Blood Flow and Metabolism

ISSN

0271678X

Volume

31

Issue

1

First Page

190

Last Page

199

PubMed ID

20517322

Digital Object Identifier (DOI)

10.1038/jcbfm.2010.76

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