Oxidative stress is associated with development and progression of cardiovascular disease. Angiotensin II produces oxidative stress and endothelial dysfunction, and its actions may be attenuated by the activity of angiotensin converting enzyme type 2 (ACE2) which converts angiotensin II to the vasoprotective peptide angiotensin (1-7). Similarly, increased oxidative stress is associated with aortic valve stenosis in humans and mice. In my thesis studies, I explore mechanisms of modulation and generation of oxidative stress in cerebral arteries and heart valves. First, I tested the hypothesis that ACE2 deficiency increases oxidative stress and vasomotor dysfunction in cerebral arteries, and examined the role of ACE2 in vascular aging. Vasomotor function was assessed in the basilar artery ex vivo of adult and old ACE2 deficient (ACE2-/y) and wild type (WT or ACE2+/y) mice. ACE2 was present, but at relatively low levels in cerebral arteries. Systolic blood pressure was similar in adult and old ACE2-/y and ACE2+/y mice. Maximal dilatation to acetylcholine was impaired in the basilar artery from adult ACE2-/y mice compared to adult ACE2+/y. In old mice, maximal vasodilatation to acetylcholine was impaired in ACE2+/y mice and severely impaired in ACE2-/y mice. The antioxidant tempol improved responses to acetylcholine in adult and old ACE2-/y and ACE2+/y mice. Nitrotyrosine staining in the basilar artery was increased in adult ACE2-/y mice and in old ACE2-/y and ACE2+/y mice relative to adult ACE2+/y, which indicates that oxidative stress was higher in cerebral arteries from ACE2 deficient mice and old mice. Expression of NADPH oxidase subunits Nox2 and p47phox, and of pro-inflammatory molecules Rcan1 and TNF alpha; was increased in cerebral arteries from old ACE2-/y and ACE2+/y mice. Additionally, I tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species (ROS). Superoxide (O2.-) was measured in heart valves from explanted human hearts that were not used for transplantation. Superoxide levels (lucigenin-enhanced chemiluminescence) were increased in homogenates of cardiac valves and pulmonary artery after incubation with serotonin. A non-specific inhibitor of flavin-oxidases (DPI), or inhibitors of monoamine oxidase-MAO (tranylcypromine and clorgyline), prevented serotonin-induced increase in O2.-. Dopamine, another MAO substrate which is increased in patients with carcinoid syndrome, also increased superoxide levels in heart valves, and this effect was attenuated by clorgyline. Apocynin did not prevent increases in O2.- during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated superoxide, and this effect was prevented by an MAO inhibitor. In conclusion, I have demonstrated that ACE2 deficiency impairs vasomotor function in cerebral arteries from adult mice and augments endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging. I have also identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.