Summary Abstract Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease. The most common cause of VCI is cerebral small vessel disease (SVD). The mechanisms underlying SVD are poorly understood, with no specific treatments currently available to prevent or treat SVD and associated VCI. We have previously found increased expression and activity of the enzyme soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem dementia and postmortem histopathological evidence of SVD. Transgenic mice expressing the human sEH gene under the endothelial Tie2 promoter (Tie2-hsEH) exhibit age-dependent cognitive deficit, supporting a causal link between endothelial sEH upregulation and cognitive impairment. sEH is responsible for the breakdown of 14,15- epoxyeicosatrienoate (14,15-EET), an endogenous lipid signaling molecule with vasodilator and vasoprotective properties that preferentially acts on small blood vessels. We recently identified G protein-coupled receptor 39 (GPR39) as a molecular target for 14,15-EET localized in human and mouse brains in peri-capillary pericytes. The current proposal will test the hypothesis that endothelial-pericyte EET/GPR39 signaling plays a protective role against aging- and SVD-related cognitive impairment by preserving capillary blood flow. In support of this hypothesis, our preliminary data shows that GPR39 knockout mice (GPR39KO) exhibit spatial memory deficit, and GPR39 SNPs in humans correlate with white matter hyperintensity volume, an MRI marker of VCI. In Aim 1, we will use male and female WT and GPR39 KO mice at 3, 12 and 18 months of age to test the hypothesis that GPR39 is upregulated in pericytes to compensate for loss of endothelial EETs in order to maintain adequate capillary flow and mitigate age-related cognitive decline. We will use unbiased, high-throughput lipidomics to characterize age-dependent changes in brain oxylipins, and phosphoproteomics to investigate changes in downstream signaling in isolated pericytes. Aim 2 will determine the role of GPR39 in cognitive impairment related to chronic cerebral hypoperfusion (CCH). We will determine if GPR39 deletion exacerbates CCH-related capillary dysfunction and cognitive impairment, which can be reversed by increasing endothelial EETs in WT, but not GPR39 KO mice. Aim 3 will determine if a GPR39 agonist can protect against cognitive impairment and capillary dysfunction in aged mice and mice with CCH. The proposed studies are highly significant and technically and conceptually innovative, as they will advance understanding of mechanisms underlying VCI, and propose a potential novel therapy for aging-related VCI.