Expression and function of β-site amyloid precursor protein-cleaving enzyme 2 in vascular endothelium.

The physiological function of β-site amyloid precursor protein-cleaving enzyme 2 (BACE2) in vascular endothelium of systemic arteries is unknown. In the present study, we generated conditional tamoxifen-inducible endothelial BACE2-deficient mice ( mice). Electron microscopic and Western blot analyses revealed that BACE2 protein is mainly present in endothelial cells of aorta. Genetic deletion of BACE2 in endothelial cells significantly impaired endothelium-dependent relaxations to Ca-ionophore A23187 in aortas as compared with tamoxifen-treated control mice, irrespective of sex. Blockade of nitric oxide synthase (NOS) with -nitro-l-arginine methyl ester abolished relaxations to A23187. In contrast, endothelium-independent relaxations to nitric oxide donor diethylamine-NONOate were unchanged. Expression of endothelial NOS protein and levels of cyclic nucleotides were also unaffected in mice. Further analysis of the mechanisms underlying impaired endothelial function demonstrated that treatment with thromboxane A receptor antagonist SQ29548 ameliorated relaxations to A23187 in the aorta of male and female mice. Furthermore, mRNA and protein expressions of cyclooxygenase-2 as well as production of thromboxane A and prostaglandin F were significantly increased in the aorta of mice. In contrast, production of 6-keto prostaglandin F and prostaglandin E was not affected. In addition, ex vivo treatment of wild-type aortas with proinflammatory cytokines decreased protein expression of BACE2. The results of our study suggest that increased production of vasoconstrictor prostanoids is responsible for impairment of endothelium-dependent relaxations to A23187 in the aorta of mice. We report a previously unrecognized role of BACE2 in the control of endothelial arachidonic acid metabolism and vasomotor function. The exact physiological role of BACE2 in endothelial function of systemic arteries is unknown. Our study shows that thromboxane A and prostaglandin F are responsible for impairment of endothelium-dependent relaxations in endothelium-specific BACE2-deficient mice. The data support an important role of BACE2 in the control of endothelial arachidonic acid metabolism and vasomotor function.