Angiotensin II and mechanisms of oxidative damage in HUVECs

Abstract

The endothelium is essential for the maintenance of vascular homeostasis. Central to this role is the production of endothelium – derived nitric oxide (EDNO), synthesized by endothelial isoform of nitric oxide synthase (eNOS). Endothelial dysfunction, manifested as impaired EDNO bioactivity, is an important early event in the development of various vascular disease, including hypertension, diabetes, genesis of tumors and atherosclerosis. Endothelial dysfunction is an early feature of atherosclerosis vascular disease, characterized by a decrease in nitric oxide (NO) bioavailability and a concomitant increase in vascular superoxide (O2 . -) formation. Loss of NO bioavailability precedes the development of overt atherosclerosis and is an independent predictor of adverse cardiovascular events. Indeed, decreased NO and enhanced production of reactive oxygen species (ROS) have been recognized as major determinants of age-associated endothelial dysfunction. The degree of impairment of EDNO bioactivity is a determinant of future vascular complications. Accordingly, growing interest exists in the pathologic mechanism involved. However it is clear that immunologic mechanisms operating in the context of common cardiovascular risk factors lead to impaired endothelial function, mainly as a consequence of decreased NO bioavailability and excessive oxidative stress. The work submitted in this thesis describes on one side studies aimed to investigate cellular mechanisms underlying endothelial dysfunction and vascular damages driven by oxidative stress in the context of aging, hypertension and atherosclerosis using in vitro models. In addition, we desired to evaluate the efficacy of reducing agents such as flavonoid to monitor whether they actually have an action to recover from the cellular oxidative damage by these natural compounds and how real is their action at the level of microcirculation in vitro models. On the other side, we present studies focused on the pathophysiology of microcirculation as far as functional aspects are concerned in the context to better understand the functioning of the Renin- Angiotensin-System in particular if the Angiotensin IV is involved in mechanisms of oxidative stress and in Calcium intracellular levels.