Abstract
BackgroundCerebral 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.ResultsCombining 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0020-0) contains supplementary material, which is available to authorized users.
Highlights
Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia
Immunohistochemistry showed a higher microvessel density in hippocampus but not in cerebral neocortex in aged Endothelial nitric oxide synthase (eNOS)+/- mice when compared with their littermate wild-type or young eNOS+/- mice (Additional file 1: Figure S1)
Spontaneous cerebral thrombosis and microinfarctions To evaluate the functionality of the hyperplasic vessels found in the aged eNOS+/- mice, cerebral fluorescent angiography was performed, which confirmed the immunohistochemical findings of increased microvascular density in hippocampus
Summary
Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. 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. Nitric oxide (NO) synthesized in endothelial cells from L-arginine by endothelial nitric oxide synthase (eNOS) is the major source of NO in brain vessels and an important signaling molecule in vasculogenesis [1,2,3], cerebral blood flow regulation [3, 4], atherosclerosis and thrombosis [5,6,7,8], and amyloid-beta (Aβ) production [9,10,11,12]. ENOS polymorphisms and haplotypes, have been reportedly associated with increased risk of cerebral small-vessel disease as well as silent brain infarction in humans [14, 15]. It should be underscored that the vast majority of work revealing pivotal roles of eNOS in pathophysiology has been conducted on young eNOS-/- mice
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