This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khurana, V. G. Articles by Katusic, Z. S. Search for Related Content PubMed PubMed Citation Articles by Khurana, V. G. Articles by Katusic, Z. S. Related Collections Cerebral Aneurysm, AVM, & Subarachnoid hemorrhage Gene therapy Endothelium/vascular type/nitric oxide

(Stroke. 2002;33:782.)
© 2002 American Heart Association, Inc.

Original Contributions

Protective Vasomotor Effects of In Vivo Recombinant Endothelial Nitric Oxide Synthase Gene Expression in a Canine Model of Cerebral Vasospasm

Vini G. Khurana, MD, PhD; Leslie A. Smith; Timothy A. Baker, BS; Daihiko Eguchi, MD, PhD; Timothy O’Brien, MD Zvonimir S. Katusic, MD, PhD

From the Departments of Molecular Pharmacology & Experimental Therapeutics (V.G.K., Z.S.K.), Neurologic Surgery (V.G.K.), Anesthesiology (L.A.S., T.A.B, D.E., Z.S.K.), and Endocrinology (T.O’B.), Mayo Clinic, Rochester, Minn.

Correspondence to Zvonimir S. Katusic, MD, PhD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: katusic.zvonimir{at}mayo.edu

Background and Purpose— Post-subarachnoid hemorrhage (SAH) cerebral vasospasm is a potentially devastating condition whose pathogenesis involves impaired nitric oxide (NO) bioavailability. We aimed to determine whether recombinant endothelial NO synthase (eNOS) gene expression may protect vasomotor function and prevent vasospasm in a canine experimental SAH model.

Methods— Recombinant adenoviral vectors (5x10⁹ plaque-forming units/animal) encoding genes for eNOS (AdeNOS) and ß-galactosidase (AdLacZ) or vehicle were injected into the cerebrospinal fluid (CSF) of dogs on day -1 (ie, 24 hours before the first intra-CSF injection of blood on day 0). Cerebral angiography was performed at day 0 (baseline) and day 7 (immediately before death), and tissues were harvested for additional studies.

Results— Western analysis and immunohistochemistry detected recombinant eNOS exclusively in cerebral arteries isolated from AdeNOS-transduced dogs, and in this group of animals CSF NO concentrations were significantly elevated by day 2. Analysis of day 7 versus day 0 cerebral angiograms for each group revealed significant spasm at the basilar artery midpoint in AdLacZ-transduced and nontransduced dogs but not in AdeNOS-transduced dogs. Isometric force recording of basilar arteries isolated from AdeNOS-transduced dogs showed significantly augmented relaxations to bradykinin and reduced contractions to endothelin-1.

Conclusions— Our results suggest that expression of recombinant eNOS in the adventitia of cerebral arteries may contribute toward protection against post-SAH vasospasm.

Key Words: basilar artery • gene therapy • nitric oxide • subarachnoid hemorrhage • vasospasm, intracranial • dogs

This article has been cited by other articles:

				W.I. Mangrum, F. Farassati, R. Kadirvel, C.P. Kolbert, S. Raghavakaimal, D. Dai, Y.H. Ding, D. Grill, V.G. Khurana, and D.F. Kallmes mRNA Expression in Rabbit Experimental Aneurysms: A Study Using Gene Chip Microarrays AJNR Am. J. Neuroradiol., May 1, 2007; 28(5): 864 - 869. [Abstract] [Full Text] [PDF]

				T. Ogawa, S. Ono, T. Ichikawa, S. Arimitsu, K. Onoda, K. Tokunaga, K. Sugiu, K. Tomizawa, H. Matsui, and I. Date Novel Protein Transduction Method by Using 11R: An Effective New Drug Delivery System for the Treatment of Cerebrovascular Diseases Stroke, April 1, 2007; 38(4): 1354 - 1361. [Abstract] [Full Text] [PDF]

				F. M. Faraci Protecting the Brain With eNOS: Run for Your Life Circ. Res., November 10, 2006; 99(10): 1029 - 1030. [Full Text] [PDF]

				A. V. R. Santhanam, L. A. Smith, K. A. Nath, and Z. S. Katusic In vivo stimulatory effect of erythropoietin on endothelial nitric oxide synthase in cerebral arteries Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H781 - H786. [Abstract] [Full Text] [PDF]

				A. V. R. Santhanam, L. A. Smith, M. Akiyama, A. G. Rosales, K. R. Bailey, and Z. S. Katusic Role of Endothelial NO Synthase Phosphorylation in Cerebrovascular Protective Effect of Recombinant Erythropoietin During Subarachnoid Hemorrhage- Induced Cerebral Vasospasm Stroke, December 1, 2005; 36(12): 2731 - 2737. [Abstract] [Full Text] [PDF]

				J. Sorenson, A. V. R. Santhanam, L. A. Smith, M. Akiyama, W. C. Sessa, and Z. S. Katusic Expression and Function of Recombinant S1179D Endothelial NO Synthase in Human Pial Arteries Stroke, January 1, 2005; 36(1): 158 - 160. [Abstract] [Full Text] [PDF]

				M. Yamaguchi, C. Zhou, D. D. Heistad, Y. Watanabe, and J. H. Zhang Gene Transfer of Extracellular Superoxide Dismutase Failed to Prevent Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage Stroke, November 1, 2004; 35(11): 2512 - 2517. [Abstract] [Full Text] [PDF]

				V. G. Khurana, Y. R. Sohni, W. I. Mangrum, R. L. McClelland, D. J. O'Kane, F. B. Meyer, and I. Meissner Endothelial Nitric Oxide Synthase T-786C Single Nucleotide Polymorphism: A Putative Genetic Marker Differentiating Small Versus Large Ruptured Intracranial Aneurysms Stroke, November 1, 2003; 34(11): 2555 - 2559. [Abstract] [Full Text] [PDF]

				C. O. Borel, A. McKee, A. Parra, M. M. Haglund, A. Solan, V. Prabhakar, H. Sheng, D. S. Warner, L. Niklason, and A. Bhardwaj Possible Role for Vascular Cell Proliferation in Cerebral Vasospasm After Subarachnoid Hemorrhage * Editorial Comment Stroke, February 1, 2003; 34(2): 427 - 433. [Abstract] [Full Text] [PDF]

				M. J. McGirt, J. R. Lynch, A. Parra, H. Sheng, R. D. Pearlstein, D. T. Laskowitz, D. A. Pelligrino, and D. S. Warner Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage Stroke, December 1, 2002; 33(12): 2950 - 2956. [Abstract] [Full Text] [PDF]