doi: 10.1161/01.str.0000152179.37900.8d
(Stroke. 2005;36:160.)
© 2005 American Heart Association, Inc.
Research Reports |
Editorial Comment: eNOS: Can We Exploit the Good?
Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
One of the major functions of vascular endothelium is to regulate tone of underlying smooth muscle. This function is mediated in large part by release of diverse endothelium-derived relaxing factors (EDRFs).1,2 A major EDRF that regulates both cerebral vascular function and structure is nitric oxide (NO) produced by the endothelial isoform of NO synthase (eNOS).1,3 Most studies indicate that NO is the predominant EDRF in the cerebral circulation.1 Although dozens of studies in animal models support this view, it is important to recall that NO is also a major EDRF in both large arteries and microvessels in the human brain.1,4
In the present study by Sorenson et al,5 the investigators examined effects of gene transfer of a mutant form of eNOS (S1179DeNOS) that is constitutively active (ie, active in the absence of agonist induced stimulation) on vascular function in human pial arteries obtained at the time of surgery. Because eNOS has many beneficial effects within the vessel wall, it was of interest to examine effects of expression of S1179DeNOS on vascular function.
Expression of S1179DeNOS increased basal levels of cyclic GMP, a key second messenger in relation to NO-mediated signaling, and reduced responses to an endothelium-dependent agonist and an NO donor. Reduced responses to NO in vessels that express S1179DeNOS probably reflects a compensatory response within vascular muscle because of increase basal levels of NO.
Reduced responses to NO in these experiments did not appear to be mediated by oxidative stress as a scavenger of the free radical superoxide had no effect on impaired responses. This observation is important as increased activity of eNOS could potentially deplete enzyme substrate (L-arginine) or cofactors (ie, tetrahydrobiopterin), resulting in ‘uncoupling’ of eNOS and production of superoxide rather than NO.
The use of viral-mediated gene transfer of NOS isoforms to study the impact of NO on the vasculature is a relatively recent experimental approach. The strategy allows testing of basic biology of the vasculature but is also attractive as it may lay the framework, or at least establish proof-of-principle, for future therapeutic applications using viral vectors. To my knowledge, only two studies have used adenoviral vectors to express any gene in human cerebral arteries.6,7 The present work suggests that gene transfer of a constitutively active form of eNOS alters vascular function in these arteries. Because the vector used appears to increase basal levels of NO without increasing superoxide levels, it may have beneficial effects in models of cerebral vascular disease. This latter possibility remains to be tested.
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1. Faraci FM, Heistad DD. Regulation of the cerebral circulation: role of endothelium. Physiological Reviews. 1998; 78: 53–97.
2. Bryan RM, You J, Golding EM, Marrelli SP. Endothelium-derived hyperpolarizing factor: a cousin to nitric oxide and prostacyclin. Anesthesiology. (In press).
3. Baumbach GL, Sigmund CD, Faraci FM. Structure of cerebral arterioles in mice deficient in expression of the gene for endothelial NO synthase. Circulation Res. 2004; 95: 822–829.
4. Elhusseiny A, Hamel E. Muscarinic –but not nicotinic –acetylcholine receptors mediate a nitric oxide-dependent dilation in brain cortical arterioles: a possible role for the M5 receptor subtype. J Cerebral Blood Flow Metabol. 2000; 20: 298–305.[CrossRef][Medline] [Order article via Infotrieve]
5. Sorenson J, Santhanam AVR, Smith LA, Akiyama M, Sessa WC, Katusic ZS. Expression and function of recombinant S1179D endothelial nitric oxide synthase in human pial arteries. Stroke. 2005; 36: 158–160.
6. Khurana VG, Smith LA, Weiler DA, Springett MJ, Parisi JE, Meyer FB, Marsh WR, O’Brien T, Katusic ZS. Adenovirus-mediated gene transfer to human cerebral arteries. J Cerebral Blood Flow Metabol. 2000; 20: 1360–1371.[CrossRef][Medline] [Order article via Infotrieve]
7. Gunnett CA, Lund DD, Howard MA, Chu Y, Faraci FM, Heistad DD. Gene transfer of inducible nitric oxide synthase impairs relaxation in human and rabbit cerebral arteries. Stroke. 2002; 33: 2292–2296.
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