Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity.
OBJECTIVE
Obesity is an increasing epidemic worldwide; however, little is known about effects of obesity produced by high-fat diet (HFD) on the cerebral circulation. The purpose of this study was to examine the functional and temporal effects of a HFD on carotid and cerebral vascular function and to identify mechanisms that contribute to such functional alterations.


METHODS
Responses of cerebral arterioles (in vivo) and carotid arteries (in vitro) were examined in C57Bl/6 (wild-type) and Nox2-deficient (Nox2(-/-)) mice fed a control (10%) or a HFD (45% or 60% kcal of fat) for 8, 12, 30, or 36 weeks.


RESULTS
In wild-type mice, a HFD produced obesity and endothelial dysfunction by 12 and 36 weeks in cerebral arterioles and carotid arteries, respectively. Endothelial function could be significantly improved with Tempol (a superoxide scavenger) treatment in wild-type mice fed a HFD. Despite producing a similar degree of obesity in both wild-type and Nox2(-/-) mice, endothelial dysfunction was observed only in wild-type, but not in Nox2(-/-), mice fed a HFD.


CONCLUSIONS
Endothelial dysfunction produced by a HFD occurs in a temporal manner and appears much earlier in cerebral arterioles than in carotid arteries. Genetic studies revealed that Nox2-derived superoxide plays a major role in endothelial dysfunction produced by a HFD. Such functional changes may serve to predispose blood vessels to reduced vasodilator responses and thus may contribute to alterations in cerebral blood flow associated with obesity.
From the Departments of Internal Medicine (C.M.L., D.A.K., F.M.F.) and Pharmacology (F.M.F.), The University of Iowa Carver College of Medicine, Iowa City, IA; Vascular Biology Center (X.C., E.M.) and Department of Physiology, Medical College of Georgia (J.F., A.E.), Georgia Regents University, Augusta, GA; Departments of Pharmacology (S.Z., J.L.F., S.P.D.) and Neurology (S.P.D.), The University of Mississippi Medical Center, Jackson, MS; and Charlie Norwood VA Medical Center, Augusta, GA (A.E.).
Cynthia M
CM
Lynch
Dale A
DA
Kinzenbaw
Xunxheng
X
Chen
Shanshan
S
Zhan
Erin
E
Mezzetti
Jessica
J
Filosa
Adviye
A
Ergul
Jessica L
JL
Faulkner
Frank M
FM
Faraci
Sean P
SP
Didion
D000821:Animal Feed; D000818:Animals; D001160:Arterioles / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D002560:Cerebrovascular Circulation; D059305:Diet, High-Fat / Q000009:adverse effects*; D006720:Homozygote; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000150:complications; D010641:Phenotype; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors
D008562:Membrane Glycoproteins; D013481:Superoxides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
brain; diabetes mellitus, type 2; diet, high-fat; oxidative stress