Deletion of microsomal epoxide hydrolase gene leads to increased density in cerebral vasculature and enhances cerebral blood flow in mice

Microsomal epoxide hydrolase (mEH), first identified as detoxifying enzyme, can hydrolyze epoxyeicosatrienoic acids (EETs) to less active diols (DHETs). EETs are potent vasodilatory and pro-angiogenic lipids, also implicated in neurovascular coupling. In mouse brain, mEH is strongly expressed in vascular and perivascular cells in contrast to the related soluble epoxide hydrolase (sEH), predominantly found in astrocytes. While sEH inhibition in stroke has demonstrated neuroprotective effects and increases cerebral blood flow (CBF), data regarding the role of mEH in brain are scarce. Here, we explored the function of mEH in cerebral vasculature by comparing mEH-KO, sEH-KO and WT mice. Basal cerebral volume (CBV $_{0}$ ) was significantly higher in various mEH-KO brain areas compared to WT and sEH-KO. In line, quantification of cerebral vasculature in cortex and thalamus revealed a higher capillary density in mEH-KO, but not in sEH-KO brain. Whisker-stimulated CBF changes were by factor two higher in both mEH-KO and sEH-KO. In acutely isolated cerebral endothelial cells the loss of mEH, but not of sEH, augmented total EET levels and decreased the DHET:EET ratio. Collectively, these data suggest an important function of mEH in the regulation of cerebral vasculature and activity-modulated CBF, presumably by controlling local levels of endothelial-derived EETs.