Role of soluble epoxide hydrolase in age-related vascular cognitive decline

• Vascular cognitive impairment (VCI) is associated with higher cerebrovascular lesion burden both on premortem MRI and postmortem histopathology.
• Levels of 14,15-dihydroxyeicosatrienoic acid (14,15-DHET) are elevated in human VCI brain tissue.
• Soluble epoxide hydrolase immunoreactivity is localized in microvascular endothelium in human brain and is higher in microvessels adjacent to lesions.
• EPHX2 polymorphism R287Q is associated with higher volume of T2-weighted white mater hyperintensity.

P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI.