Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease (AD). Unfortunately, VCI remains poorly understood, with no specific treatment, in part due to lack of understanding of underlying mechanisms of the disease. The most common cause of VCI is cerebral small vessel disease (SVD), an age-related vasculopathy primarily affecting deep penetrating end-arterioles supplying subcortical gray and periventricular and deep white matter. SVD is seen radiologically as isolated lacunar infarcts or diffuse ischemic white matter lesions (WML, called leukoaraiosis). WML are common in the elderly brain and are particularly prevalent in aging-related neurodegenerative disorders, including AD and VCI. The most consistent pathological finding in WML is cerebral microangiopathy, pathological changes in small intraparenchymal cerebral arterioles, which may lead to foci of chronic hypoperfusion and subsequent ischemic changes in white matter. The mechanisms underlying VCI and SVD in particular are poorly understood, and no specific treatments currently exist to prevent or treat SVD and associated VCI. There is evidence, however, that SVD involves endothelial injury and dysfunction. Accumulating evidence suggests that dilation of large vessels is primarily regulated by the endothelium-derived nitric oxide (NO), whereas in small vessels, it is additionally regulated by the endothelium-dependent hyperpolarizing factor (EDHF), which plays a particularly important role in small vessels after injury. Evidence from several vascular beds, including heart suggests that a group of endothelial-derived lipid signaling molecules called EETs (epoxyeicosatrienoic acids) may mediate EDHF response in the microcirculation. In addition to being vasodilators, EETs have neuroprotective properties, and protect neurons and glia from ischemic injury. Our preliminary data in postmortem human tissue from patients with SVD demonstrate that the enzyme that metabolizes and inactivates EETs, called soluble epoxide hydrolase (sEH), is upregulated in small cerebral vessels in SVD. Upregulation of sEH reduces the bioavailability of EETs in the microenvironment surrounding these vessels, rendering downstream and neighboring cells susceptible to hypoxic ischemic injury. In the current proposal, we will use a mouse model of chronic cerebral hypoperfusion to determine if sEH is causally and mechanistically involved in cerebrovascular pathology and neurocognitive decline in VCI. We will test the hypothesis that chronic hypoperfusion induces microvascular sEH expression, which further reduces tissue perfusion and leads to WML and cognitive impairment, and that mice with endothelial-specific expression of human sEH will exhibit accelerated age-dependent vascular pathology, WML and neurocognitive decline, while mice with sEH inhibition and gene deletion will be protected.

Public Health Relevance

Vascular dementia, or vascular cognitive impairment (VCI), is the second most common cause of dementia after Alzheimer's disease (AD), but the underlying mechanism is unknown and no specific therapy currently available for VCI. The proposal will investigate the role of a specific enzyme, called soluble epoxide hydrolase (sEH), in VCI, which may lead to the development of disease-specific and mechanism-based treatment for VCI. The proposed studies may also lead to the development of genetic and biochemical biomarkers to predict and diagnose VCI.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG043857-01A1
Application #
8583819
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Petanceska, Suzana
Project Start
2013-07-15
Project End
2015-04-30
Budget Start
2013-07-15
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$231,000
Indirect Cost
$81,000
Name
Oregon Health and Science University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Zhang, Wenri; Davis, Catherine M; Edin, Matthew L et al. (2013) Role of endothelial soluble epoxide hydrolase in cerebrovascular function and ischemic injury. PLoS One 8:e61244

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