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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Petanceska, Suzana
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Oregon Health and Science University
Schools of Medicine
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Davis, Catherine M; Liu, Xuehong; Alkayed, Nabil J (2017) Cytochrome P450 eicosanoids in cerebrovascular function and disease. Pharmacol Ther 179:31-46
Johnson, Lance A; Zuloaga, Kristen L; Kugelman, Tara L et al. (2016) Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma. EBioMedicine 3:26-42
Zuloaga, Kristen L; Zhang, Wenri; Yeiser, Lauren A et al. (2015) Neurobehavioral and imaging correlates of hippocampal atrophy in a mouse model of vascular cognitive impairment. Transl Stroke Res 6:390-8
Siler, Dominic A; Gonzalez, Jorge A; Wang, Ruikang K et al. (2014) Intracisternal administration of tissue plasminogen activator improves cerebrospinal fluid flow and cortical perfusion after subarachnoid hemorrhage in mice. Transl Stroke Res 5:227-37
Benedek, Gil; Zhu, Wenbin; Libal, Nicole et al. (2014) A novel HLA-DR?1-MOG-35-55 construct treats experimental stroke. Metab Brain Dis 29:37-45
Zuloaga, Kristen L; Davis, Catherine M; Zhang, Wenri et al. (2014) Role of aromatase in sex-specific cerebrovascular endothelial function in mice. Am J Physiol Heart Circ Physiol 306:H929-37
Nelson, Jonathan W; Young, Jennifer M; Borkar, Rohan N et al. (2014) Role of soluble epoxide hydrolase in age-related vascular cognitive decline. Prostaglandins Other Lipid Mediat 113-115:30-7
Jia, Jia; Xiao, Yunqi; Wang, Wei et al. (2013) Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress. Neurochem Int 62:1072-8
Jouihan, Sari A; Zuloaga, Kristen L; Zhang, Wenri et al. (2013) Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus. J Cereb Blood Flow Metab 33:1650-6
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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