Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment

Xing Lin Tan, Yue Qiang Xue, Tao Ma, Xiaofang Wang, Jing Jing Li, Lubin Lan, Kafait Malik, Michael Mcdonald, Alejandro Dopico, Francesca-Fang Liao

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37 Citations (Scopus)

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.

Original languageEnglish (US)
Article number24
JournalMolecular Neurodegeneration
Volume10
Issue number1
DOIs
StatePublished - Jun 24 2015

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Cerebral Amyloid Angiopathy
Nitric Oxide Synthase Type III
Cerebral Infarction
Blood Vessels
Alzheimer Disease
Stroke
Amyloid
Dementia
Cognitive Dysfunction
Cerebral Angiography
Vascular Dementia
Brain Ischemia
Blood-Brain Barrier
Vascular Diseases

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment. / Tan, Xing Lin; Xue, Yue Qiang; Ma, Tao; Wang, Xiaofang; Li, Jing Jing; Lan, Lubin; Malik, Kafait; Mcdonald, Michael; Dopico, Alejandro; Liao, Francesca-Fang.

In: Molecular Neurodegeneration, Vol. 10, No. 1, 24, 24.06.2015.

Research output: Contribution to journalArticle

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AU - Xue, Yue Qiang

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AU - Li, Jing Jing

AU - Lan, Lubin

AU - Malik, Kafait

AU - Mcdonald, Michael

AU - Dopico, Alejandro

AU - Liao, Francesca-Fang

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AB - 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.

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