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Abstract
Soluble Epoxide Hydrolase (sEH) is a key enzyme in the metabolism and termination of action of epoxyeicosatrienoic acids, derivatives of arachidonic acid, which are protective against ischemic stroke. Mice lacking sEH globally are protected from injury following stroke; however, little is known about the role of endothelial sEH in brain ischemia. We generated transgenic mice with endothelial-specific expression of human sEH (Tie2-hsEH), and assessed the effect of transgenic overexpression of endothelial sEH on endothelium-dependent vascular reactivity and ischemic injury following middle cerebral artery occlusion (MCAO). Compared to wild-type, male Tie2-hsEH mice exhibited impaired vasodilation in response to stimulation with 1 µM acetylcholine as assessed by laser-Doppler perfusion monitoring in an in-vivo cranial window preparation. No difference in infarct size was observed between wild-type and Tie2-hsEH male mice. In females, however, Tie2-hsEH mice sustained larger infarcts in striatum, but not cortex, compared to wild-type mice. Sex difference in ischemic injury was maintained in the cortex of Tie2-hsEH mice. In the striatum, expression of Tie2-hsEH resulted in a sex difference, with larger infarct in females than males. These findings demonstrate that transgenic expression of sEH in endothelium results in impaired endothelium-dependent vasodilation in the cerebral circulation, and that females are more susceptible to enhanced ischemic damage as a result of increased endothelial sEH than males, especially in end-arteriolar striatal region.
Highlights
Epoxyeicosatrienoic acids (EETs) produced in brain play an important role in cerebral blood flow regulation [1]
These mice displayed increased plasma levels of the EETs hydrolysis products, dihydroxyeicosatrienoic acids (DHETs), as measured by LC-MS/MS. 14,15DHETs were increased from 168.68 pg/ml in Wild type (WT) to 317.07 pg/ ml in Tie2-hsEH expressing mice and 11,12-DHETs were increased from 99.94 pg/ml to 164.94 pg/ml, respectively (Figure 1D) (n = 8 WT, n = 13 Tie2-hsEH, P,0.05)
Medium collected from aortic endothelial cell cultures from Tie2-hsEH mice had lower arachidonic acid and linoleic acid epoxide:diol ratios (14,15-EET:DHET and 12,13-EpOME:DiHOME) as measured by LC-MS/MS, both of which serve as readouts of increased soluble epoxide hydrolase (sEH) function (Figure 1D) (n = 3, P,0.05)
Summary
Epoxyeicosatrienoic acids (EETs) produced in brain play an important role in cerebral blood flow regulation [1]. They are protective against ischemic stroke in vivo and against ischemiainduced cell death in vitro in multiple brain- derived cell types including neurons, astrocytes and endothelial cells [2,3,4,5]. The risk of stroke in women greatly increases following menopause [9,10] This gender difference has been attributed largely to sex hormones, with estrogen in particular affording protection to premenopausal females [11,12]. Upon ovariectomy of wild-type female mice infarct volumes increase to male levels, ovariectomized females with genetic ablation of sEH no longer exhibit increased infarct volumes, indicating that ovarian sex hormones contribute to the protection observed in the intact female mice, presumably by decreasing sEH levels [7]
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