The role of oxidative stress and NADPH oxidase in cerebrovascular disease

Abstract

The study of reactive oxygen species (ROS) and oxidative stress remains a very active area of biological research, particularly in relation to cellular signaling and the role of ROS in disease. In the cerebral circulation, oxidative stress occurs in diverse forms of disease and with aging. Within the vessel wall, ROS produce complex structural and functional changes that have broad implications for regulation of cerebral perfusion and permeability of the blood-brain barrier. These oxidative-stress-induced changes are thought to contribute to the progression of cerebrovascular disease. Here, we highlight recent findings in relation to oxidative stress in the cerebral vasculature, with an emphasis on the emerging role for NADPH oxidases as a source of ROS and the role of ROS in models of disease.

Figure 1

Schematic illustration of the interrelationships of various ROS and NO. NO produced by endothelial eNOS is normally a major signaling molecule. Superoxide (O₂⁻) is produced from molecular oxygen (O₂) by a variety of sources including NADPH oxidases (Nox). Once formed, superoxide can directly produce injury (not shown), can be converted by SOD into H₂O₂ or can react with NO to form peroxynitrite (ONOO⁻). The NADPH oxidase containing Nox4 can produce H₂O₂ directly. H₂O₂ is an important signaling molecule. In combination with Fe²⁺,. H₂O₂ can form the hydroxyl radical (OH·), a highly reactive ROS that causes cellular injury. H₂O₂ can also be degraded by glutathione peroxidase (GPx) or catalase (Cat). In addition, peroxynitrite can produce further increases in superoxide and oxidative stress by inhibiting the activity of SOD (not shown) or by oxidizing tetrahydrobiopterin, resulting in an uncoupling of eNOS where eNOS produces superoxide instead of NO (see text for further detail). Superoxide can also react with arachidonic acid and produce isoprostanes (not shown).

Figure 2

Schematic of structural changes in cerebral arterioles shown in cross-section. During disease or in response to genetic manipulation, vessels can undergo hypertrophy [increase cross-sectional area (CSA)] and/or exhibit remodeling (inward or outward changes in diameter). During angiotensin-II-dependent hypertension and in response to interference with PPARγ function (following expression of a dominant-negative variant in PPARγ), both hypertrophy and inward remodeling occur. By contrast, hypertrophy occurs in the absence of inward remodeling in models of angiotensin-II-independent hypertension (BPH-2 mice, a genetic model of hypertension thought to be renin-independent), hyperhomocysteinemia, in response to treatment with a NOS inhibitor (L-NAME), or genetic deficiency in eNOS or CuZn-SOD (SOD1). See text for additional details. Illustration based on data from Refs (, , –47).

Figure 3

Schematic representation of components of the vascular NADPH oxidases (based on Refs , –59). Nox1 is activated by homologs ofp47^phox and p67^phox – Nox-organizer 1 (NoxO1) and Nox-activator 1 (NoxA1). Nox2 requires recruitment ofp47^phox and p67^phox. Nox4 does not appear to require any cytosolic subunits, and Nox5 is activated by Ca²⁺. Nox1, Nox2 and Nox4 require association with p22^phox to function normally. Nox4 might produce H₂O₂ directly (58). The subcellular localization of Nox isoforms and the site of superoxide generation varies with cell type and presumably function (2). While some isoforms are expressed in the cell membrane, additional sites of expression include the nucleus (or perinuclear) and the endoplasmic reticulum.