title: Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging.
abstract: OBJECTIVE
  Angiotensin II produces oxidative stress and endothelial dysfunction in cerebral arteries, and angiotensin II type I receptors may play a role in longevity and vascular aging. Angiotensin-converting enzyme type 2 (ACE2) converts angiotensin II to angiotensin (1-7) and thus, may protect against effects of angiotensin II. We hypothesized that ACE2 deficiency increases oxidative stress and endothelial dysfunction in cerebral arteries and examined the role of ACE2 in age-related cerebrovascular dysfunction.
  
  
  METHODS
  Endothelial function, expression of angiotensin system components, NADPH oxidase subunits, and proinflammatory cytokines were examined in cerebral arteries from adult (12 months old) and old (24 months old) ACE2 knockout (KO) and wild-type (WT) mice. The superoxide scavenger tempol was used to examine the role of oxidative stress on endothelial function.
  
  
  RESULTS
  Vasodilatation to acetylcholine was impaired in adult ACE2 KO (24±6% [mean±SE]) compared with WT mice (52±7%; P<0.05). In old mice, vasodilatation to acetylcholine was impaired in WT mice (29±6%) and severely impaired in ACE2 KO mice (7±5%). Tempol improved endothelial function in adult and old ACE2 KO and WT mice. Aging increased mRNA for tumor necrosis factor-α in WT mice, and significantly increased mRNA levels of NAPDH oxidase 2, p47(phox), and Regulator of calcineurin 1 in both ACE2 KO and WT mice. mRNA levels of angiotensin system components did not change during aging.
  
  
  CONCLUSIONS
  ACE2 deficiency impaired endothelial function in cerebral arteries from adult mice and augmented endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging.
authors.affiliation: Department of Pharmacology, University of Iowa, College of Medicine, 500 Newton Road, 340B EMRB, Iowa City, IA 52242, USA. ricardo-pena@uiowa.edu
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Peña Silva
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Mitchell
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000803:Angiotensin I / Q000096:biosynthesis; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002536:Cerebral Arteries / Q000201:enzymology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000096:biosynthesis; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D012333:RNA, Messenger; D014665:Vasodilator Agents; D000804:Angiotensin II; D000803:Angiotensin I; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D000109:Acetylcholine