title: Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals.
abstract: Angiotensin II (Ang II) exerts detrimental effects on cerebral circulation, the mechanisms of which have not been elucidated. In particular, Ang II impairs the increase in cerebral blood flow (CBF) produced by neural activity, a critical mechanism that matches substrate delivery with energy demands in brain. We investigated whether Ang II exerts its deleterious actions by activating Ang II type 1 (AT1) receptors on cerebral blood vessels and producing reactive oxygen species (ROS) through NADPH oxidase. Somatosensory cortex CBF was monitored in anesthetized mice by laser-Doppler flowmetry. Ang II (0.25 microg/kg per minute IV) attenuated the CBF increase produced by mechanical stimulation of the vibrissae. The effect was blocked by the AT1 antagonist losartan and by ROS scavenger superoxide dismutase or tiron and was not observed in mice lacking the gp91phox subunit of NADPH oxidase or in wild-type mice treated with the NADPH oxidase peptide inhibitor gp91ds-tat. Ang II increased ROS production in cerebral microvessels, an effect blocked by the ROS scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin and by the NADPH oxidase assembly inhibitor apocynin. Ang II did not increase ROS production in gp91-null mice. Double-label immunoelectron microscopy demonstrated that AT1 and gp91phox immunoreactivities were present in endothelium and adventitia of neocortical arterioles. Collectively, these findings suggest that Ang II impairs functional hyperemia by activating AT1 receptors and inducing ROS production via a gp91phox containing NADPH oxidase. The data provide the mechanistic basis for the cerebrovascular dysregulation induced by Ang II and suggest novel therapeutic strategies to counteract the effects of hypertension on the brain.
authors.affiliation: Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Kazama
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Helene
authors.initials: H
authors.lastname: Girouard
authors.forename: Kelly
authors.initials: K
authors.lastname: Frys
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000633:toxicity*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D045303:Cytochromes b / Q000172:deficiency / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D006023:Glycoproteins / Q000494:pharmacology; D006935:Hypercapnia / Q000503:physiopathology; D006940:Hyperemia / Q000503:physiopathology*; D006973:Hypertension / Q000139:chemically induced; D017078:Laser-Doppler Flowmetry; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D013482:Superoxide Dismutase / Q000494:pharmacology; D014738:Vibrissae / Q000502:physiology*
chemical_list: D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D016166:Free Radical Scavengers; D005609:Free Radicals; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D008665:Metalloporphyrins; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; C473031:gp91ds-tat protein, chimeric; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D000804:Angiotensin II; D011092:Polyethylene Glycols; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D026423:S-Nitroso-N-Acetylpenicillamine; D045303:Cytochromes b; C056165:acetovanillone; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; C488842:Cybb protein, mouse; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019808:Losartan