Modeling the effects of superoxide production on the cerebral blood flow.

Abstract

Oxidative stress with the associated endothelial cell dysfunction is an important pathophysiological mechanism for the hypertension induced vascular dysfunction and end organ damage. The oxidant stress leads to the impairment of nitric oxide synthesis, release and/or activity through multiple pathways which are all part of endothelial cells dysfunction. In the brain, this has been closely linked with the hypertension induced neurovascular dysfunction and impairment of cerebral blood flow regulation. The superoxide anion interacts with nitric oxide resulting in decreasing its bioavailability while generating the harmful perioxynitrite which contributes to the cellular oxidative damage. In this work, we develop a mathematical model representing the effects of nitric oxide and superoxide production and their interactions on changes of cerebral blood flow. Our model integrates and extends prior work through modeling the effects of nitric oxide and superoxide generation, diffusion and degradation on cerebral blood flow. Our results show that superoxide production attenuates the increase of cerebral blood flow mediated by nitric oxide production and explains the prior experimental observations. While strategies to increase nitric oxide production may alleviate the superoxide dependent decrease in cerebral blood flow, our model predicts an associated increase of perioxynitrite production leading to oxidative cellular injury. Our work provides a mathematical modeling platform that may be used to integrate the different cellular processes regulating the cellular response to oxidant stress. This platform can be utilized to test future therapeutics aiming to reduce the cerebrovascular oxidative stress related injuries and improve cerebral blood flow.