Nox, Reactive Oxygen Species and Regulation of Vascular Cell Fate

Abstract

The generation of reactive oxygen species (ROS) and an imbalance of antioxidant defence mechanisms can result in oxidative stress. Several pro-atherogenic stimuli that promote intimal-medial thickening (IMT) and early arteriosclerotic disease progression share oxidative stress as a common regulatory pathway dictating vascular cell fate. The major source of ROS generated within the vascular system is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (Nox), of which seven members have been characterized. The Nox family are critical determinants of the redox state within the vessel wall that dictate, in part the pathophysiology of several vascular phenotypes. This review highlights the putative role of ROS in controlling vascular fate by promoting endothelial dysfunction, altering vascular smooth muscle phenotype and dictating resident vascular stem cell fate, all of which contribute to intimal medial thickening and vascular disease progression.

Keywords: Nox; ROS; adventitial cells; arteriosclerotic disease; endothelial; intimal-medial thickening; stem cells; vascular smooth muscle.

Figure 1

Nox enzymes within the vasculature. The schematic depicts the Nox enzymes within the vascular wall. All three layers of the vascular wall [intima (i.e., endothelial cells), media (i.e., smooth muscle cells), and adventitia (i.e., fibroblasts and macrophages)] express Nox family members. Nox4 is the predominant isoform in endothelial cells, Nox1 and Nox4 in smooth muscle cells, Nox4 in fibroblasts, and Nox2 and Nox4 in stem cells. Nox-derived O₂⁻ avidly reacts with NO. Nox-derived ROS also affect the extracellular matrix and the external (EEL) and internal elastic lamina (IEL), influence gene expression and are involved in cell proliferation, migration and differentiation that lead to vascular disease progression [55].

Figure 2

Simplified schematic of common forms of Nox enzymes in endothelial cells. H₂O₂ can be converted to H₂O by catalase (CAT) or glutathione peroxidase (GPx). O₂⁻ can also react with NO to generate the reactive nitrogen species ONOO⁻ that could be converted into NO₂·, which reacts with protein tyrosine residues to generate NO₂-Tyr. This reaction can lead to a decrease in the bioavailability of NO, leading to endothelial dysfunction. Nox-derived ROS may also control endothelial-mesenchymal stem cell transition (EndoMT) [36].

Figure 3

Simplified schematic of common forms of Nox enzymes in vascular smooth muscle cell (vSMCs). Nox4, once activated, generates H₂O₂. Nox1 expression is increased early and decreased with lesion progression, while induction of Nox4 is a late event. Nox2 and p22phox are elevated throughout lesion development. SMCs have increased generation of ROS, cell cycle arrest, evidence of senescence, and increased susceptibility to apoptosis [69].

Figure 4

Simplified schematic of common forms of Nox enzymes in adventitial cells. Nox2 and p22phox are predominant in the adventitia of hypertensive vessels and promote the secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin 6 (IL-6). Nox1 and Nox4 with Nox4-derived H₂O₂ considered protective are also present [87].

Figure 5

Simplified schematic of common forms of Nox enzymes in multipotent (mesenchymal stem cell (MSC)-like cells. Proliferative, self-renewing multipotent vascular progenitors with phenotypic characteristics of neural stem cells maintain a high ROS status and are highly responsive to ROS stimulation. ROS-mediated self-renewal and differentiation is dependent on PI3K/AKT signalling and underlies a redox-mediated regulatory mechanism of stem cell function and vascular repair [109].