Effects of angiotensin II on the cerebral circulation: role of oxidative stress

Abstract

Oxidative stress has emerged as a key component of many diseases that affect the vasculature. Oxidative stress is characterized as a cellular environment where the generation of oxidant molecules overwhelms endogenous anti-oxidant defense mechanisms. NADPH oxidases are a family of enzymes whose primary purpose is generation of reactive oxygen species (oxidant molecules) and therefore are likely to be key contributors to oxidative stress. Hypertension is associated with oxidative stress in the vasculature and is a major risk factor for stroke and cognitive abnormalities. Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS) and plays a critical role in promoting oxidative stress in the vasculature. In the cerebral circulation, Ang II has been implicated in reactive oxygen species generation, alterations to vasomotor function, impaired neurovascular coupling, inflammation, and vascular remodeling. Furthermore, studies in humans have shown that cerebral blood flow is altered during hypertension and therapeutically targeting the RAS improves cerebral blood flow. Importantly, many of the aforementioned effects have been shown to be dependent on NADPH oxidases. Thus, Ang II, NADPH oxidases and oxidative stress are likely to play key roles in the pathogenesis of hypertension and associated cerebrovascular disease. This review will focus on our current understanding of the contribution of Ang II and NADPH oxidases to oxidative stress in the cerebral circulation.

Keywords: NADPH oxidase; cerebral arteries; cerebral blood flow; endothelium; neurovascular coupling; nitric oxide.

Figure 1

Interactions between nitric oxide (NO^·) and reactive oxygen species (ROS). NO^· is a critical component of mechanisms that regulate cerebrovascular homeostasis. Diverse stimuli (including shear stress, neurotransmitters like acetylcholine and activation of neurons) can result in the generation of NO^· by either endothelial or neuronal nitric oxide synthase (eNOS and nNOS, respectively). The generation of NO^· is dependent on the presence of the substrate L-arginine (L-Arg) and enzyme co-factors including tetrahydrobiopterin (BH₄). NO^· activates its receptor in vascular muscle soluble guanylate cyclase (sGC), which results in the formation of cyclic guanosine monophosphate (cGMP). This results in numerous signaling events and functional effects which include cerebral vasodilation. NADPH oxidases (Nox1 and Nox2) generate superoxide (O₂^·−) and Nox4 can generate hydrogen peroxide (H₂O₂), ROS can then participate in signaling events, but may also cause cellular injury. O₂^·− is a potent scavenger of NO^·, which reduces the bioavailability of NO^· and results in the formation of peroxynitrite (ONOO⁻), which also causes cellular injury. H₂O₂ can react with heavy metals to form the highly reactive and toxic hydroxyl radical (OH^·).

Figure 2

Angiotensin II (Ang II) promotes oxidative stress in the vasculature via stimulation of AT1 receptors and subsequent activation of NADPH oxidases. Oxidative stress contributes to blood-brain barrier (BBB) dysfunction, impairment of vasodilation and neurovascular coupling, and promotes inward vascular remodeling and inflammation. Overall, these effects contribute to reductions in cerebral blood flow, which can lead to dementia and increased susceptibility for stroke and lessen recovery following stroke or other forms of brain injury.