Microvascular NADPH oxidase in health and disease

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Abstract

The systemic and cerebral microcirculation contribute critically to regulation of local and global blood flow and perfusion pressure. Microvascular dysfunction, commonly seen in numerous cardiovascular pathologies, is associated with alterations in the oxidative environment including potentiated production of reactive oxygen species (ROS) and subsequent activation of redox signaling pathways. NADPH oxidases (Noxs) are a primary source of ROS in the vascular system and play a central role in cardiovascular health and disease. In this review, we focus on the roles of Noxs in ROS generation in resistance arterioles and capillaries, and summarize their contributions to microvascular physiology and pathophysiology in both systemic and cerebral microcirculation. In light of the accumulating evidence that Noxs are pivotal players in vascular dysfunction of resistance arterioles, selectively targeting Nox isozymes could emerge as a novel and effective therapeutic strategy for preventing and treating microvascular diseases.

Graphical abstract

Major Nox-mediated redox-sensitive signaling pathways involved in microvascular physiology and pathophysiology. Schematic diagram illustrating known Nox and ROS-mediated signaling pathways in cerebral and systemic microvascular endothelium and smooth muscle. Arrows denote positive activation of downstream targets. Blunt-ended arrows indicate inhibitory effects on targets. Dashed arrows denote pathways that are active in other vascular system but have not been reported in the microcirculation. In endothelial cells, Noxs can be activated by hormones, cytokines, growth factors and oscillatory shear stress [248,249], which stimulate ROS-dependent pathways that eventually lead to increased angiogenesis, inflammation, BBB permeability and impaired neurovascular coupling. Interaction between superoxide anion and NO produces peroxynitrite, which reduces NO bioavailability and causes endothelial dysfunction. In smooth muscle cells of cerebral and systemic arterioles, Noxs can be stimulated by mechanical stretch as well as vasoactive agents, e.g. AngII. Nox-derived ROS is centrally involved in inhibiting potassium channels, activating protein kinases and increasing Ca2+ sensitivity of the contractile apparatus. These effects are physiologically important for myogenic tone regulation, but may also lead to augmented vasoconstriction and diminished vasorelaxation. Microvascular remodeling is also dependent on Nox-mediated ROS production through putative stimulation of MMPs.Abbreviations: O2• −: superoxide anion; H2O2: hydrogen peroxide; SOD: superoxide dismutase; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; ONOO−: peroxynitrite; p38: p38 mitogen-activated protein kinases; JNK: c-Jun N-terminal kinases; ERK: extracellular signal-regulated kinases; HIF1α: hypoxia-inducible factor 1-alpha; AMPK: 5′AMP-activated protein kinases; NFκB: nuclear factor-κB; GPCRs: G protein-coupled receptors; TRP channels: transient receptor potential channels; PKC: protein kinase C; ROCK: rho-associated protein kinase; ROS: reactive oxygen species; BK: big-conductance Ca2+-activated K+ channels; Kv: voltage-gated K+ channels; PKG: cGMP-dependent protein kinase; GTP: guanosine triphosphate; cGMP: cyclic guanosine monophosphate; sGC: soluble guanylyl cyclase; MMP: matrix metalloproteinases.

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