Vascular phenotype of amyloid precursor protein-deficient mice

Abstract

The amyloid precursor protein (APP) is expressed in the blood vessel wall, but the physiological function of APP is not completely understood. Previous studies established that APP has amine oxidase activity responsible for degradation of catecholamines. In the present study, we characterized the vascular phenotype of APP-knockout (APP−/−) mice. We demonstrate that circulating levels of catecholamines are significantly increased in male as compared with female APP−/− mice. Studies of vasomotor function in isolated aortas revealed that contractions to the α1-receptor agonist phenylephrine were significantly reduced in male APP−/− mice but not in females. In addition, contractions to G protein activation with sodium fluoride were reduced exclusively in male APP−/− mice aortas. The endothelium-dependent relaxations to acetylcholine were not affected by the loss of APP in mice of both sexes. Further analysis of the mechanisms underlying endothelium-dependent relaxations revealed that inhibition of cyclooxygenase by indomethacin significantly impaired relaxations to acetylcholine exclusively in male APP−/− mice. Furthermore, acetylcholine-induced production of cyclic guanosine monophosphate (cGMP) was significantly reduced in male APP−/− mice aortas while acetylcholine-induced production of cyclic adenosine monophosphate (cAMP) was enhanced. We concluded that altered vascular reactivity to phenylephrine appears to be in part the result of chronic exposure of male APP−/− aorta to high circulating levels of catecholamines. The mechanisms responsible for the impairment of endothelium-dependent cGMP signaling and adaptive enhancement of endothelium-dependent production of cAMP remain to be defined. NEW & NOTEWORTHY Male amyloid precursor protein (APP)-deficient mice have higher circulating levels of catecholamines as compared with female APP-deficient mice. As a consequence, endothelium-dependent and endothelium-independent vasomotor functions of male APP-deficient mice are significantly altered. Under physiological conditions, expression of APP appears to play an important role in vascular function.