Baumbach GL, Sigmund CD, Faraci FMStructure of cerebral arterioles in mice deficient in expression of the gene for endothelial nitric oxide synthase. Circ Res 95:822-829

Department of Pathology, 5231D RCP, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Circulation Research (Impact Factor: 11.02). 10/2004; 95(8):822-9. DOI: 10.1161/01.RES.0000146279.11923.14
Source: PubMed


We examined effects of pharmacological inhibition of nitric oxide synthase (NOS) and genetic deficiency of the endothelial isoform of NOS (eNOS) on structure and mechanics of cerebral arterioles. We measured pressure, diameter, and cross-sectional area (CSA) of the vessel wall (histologically) in maximally dilated cerebral arterioles in mice that were untreated or treated for 3 months with the NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg per day in drinking water). Treatment with L-NAME increased systemic arterial mean pressure (SAP; 143+/-4 versus 121+/-4 mm Hg, P<0.05) and CSA (437+/-27 versus 310+/-34 microm2, P<0.05). These findings suggest that hypertension induced in mice by NOS inhibition is accompanied by hypertrophy of cerebral arterioles. To determine the role of the eNOS isoform in regulation of cerebral vascular growth, we examined mice with targeted disruption of one (heterozygous) or both (homozygous) genes encoding eNOS. Wild-type littermates served as controls. SAP and CSA were significantly increased in homozygous (SAP, 141+/-5 versus 122+/-3 mm Hg in wild-type mice, P<0.05; CSA, 410+/-18 versus 306+/-15 microm2 in wild-type mice, P<0.05), but not in heterozygous (SAP, 135+/-4 mm Hg; CSA, 316+/-32 microm2) eNOS-deficient mice. Carotid ligation normalized cerebral arteriolar pulse pressure did not prevent increases in CSA in homozygous eNOS-deficient mice. Thus, cerebral arterioles undergo hypertrophy in homozygous eNOS-deficient mice, even in the absence of increases in arteriolar pulse pressure. These findings suggest that eNOS plays a major role in regulation of cerebral vascular growth.

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    • "L-NAME (10 mg/kg/day, 4 weeks) was given in drinking water to WT (í µí±› = 16) and Nox2-/y (í µí±› = 16) mice. This dose regimen has been shown to induce hypertrophy in cerebral arterioles [17]. The treatment was started the same day after aortic banding. "
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    ABSTRACT: Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice. Mice were given N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or vehicle to drink. We measured the reactivity in cerebral arterioles through open cranial window in anesthetized mice and wall cross-sectional area and superoxide levels ex vivo. Aortic constriction increased systolic and pulse pressures in right-sided carotid arteries in all groups of mice. Ethidium fluorescence showed increased superoxide in right-sided cerebral arterioles in WT, but not in Nox2-/y mice. Dilation to acetylcholine, but not sodium nitroprusside, was reduced, and cross-sectional areas were increased in the right-sided arterioles in WT, but were unchanged in Nox2-/y mice. L-NAME reduced dilation to acetylcholine but did not result in hypertrophy in right-sided arterioles of Nox2-/y mice. In conclusion, hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide.
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    ABSTRACT: Mutation of serine 1179 to aspartate on the endothelial NO synthase (eNOS) increases NO production in the absence of stimulation by agonists. The present study was designed to determine the effect of recombinant S1179DeNOS gene expression on the vasomotor function of human pial arteries. Pial arteries were isolated from 28 patients undergoing temporal lobectomy for intractable seizures. Adenoviral vectors (10(10) pfu/mL) encoding beta-galactosidase (AdCMVLacZ) or S1179DeNOS (AdCMVS1179DeNOS) were used for ex vivo gene transfer, and vasomotor function was evaluated in control and transduced arteries. Contractions to cumulative additions of U46619 were not affected by expression of LacZ or S1179DeNOS. Endothelium-dependent relaxations to bradykinin or endothelium-independent relaxations to Diethylaminodiazen-1-ium-1,2-dioate were significantly reduced in arteries expressing S1179DeNOS. A superoxide dismutase mimetic, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, failed to improve the reduced relaxations to bradykinin. The levels of cGMP were significantly elevated in arteries expressing S1179DeNOS. Our results support the concept that high local production of NO in pial arterial wall causes adaptive reduction of vasodilator reactivity to NO.
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