title: Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment.
abstract: BACKGROUND
  Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer's disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS(+/-) mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels.
  
  
  RESULTS
  Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS(+/-) mice as early as 3-6 months of age but not in eNOS(+/+) mice at any age. Remarkably, vascular occlusions in eNOS(+/-) mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS(+/-) mice.
  
  
  CONCLUSIONS
  These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS(+/-) mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Xing-Lin
authors.initials: XL
authors.lastname: Tan
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Yue-Qiang
authors.initials: YQ
authors.lastname: Xue
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.|Department of Neurology, Wuxi Second People Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, Jiangsu province, 214002, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.|Department of Cardiology, The First Affiliated Hospital, Zhengzhou University, No.1 Jianshe road, Zhengzhou, Henan province, 450052, PR China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Lubin
authors.initials: L
authors.lastname: Lan
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
authors.affiliation: Neurology & Neurobiology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.|Anatomy & Neurobiology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: McDonald
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA.
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Dopico
authors.affiliation: Departments of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN, 38163, USA. fliao@uthsc.edu.
authors.forename: Francesca-Fang
authors.initials: FF
authors.lastname: Liao
mesh_terms: D000375:Aging; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000473:pathology; D002544:Cerebral Infarction / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D002560:Cerebrovascular Circulation; D003072:Cognition Disorders / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000503:physiopathology; D005786:Gene Expression Regulation; D006579:Heterozygote; D006624:Hippocampus / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D018782:Maze Learning; D008569:Memory Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D010296:Parietal Lobe / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013702:Temporal Lobe / Q000098:blood supply / Q000201:enzymology / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse