Detrimental role of pericyte Nox4 in the acute phase of brain ischemia

Nishimura, Ataru; Ago, Tetsuro; Kuroda, Junya; Arimura, Koichi; Terabe, Masaki; Nakamura, Kuniyuki; Wakisaka, Yoshinobu; Sadoshima, Junichi; Iihara, Koji; Kitazono, Takanari

doi:10.1177/0271678x15606456

Cited by 67 publications

(62 citation statements)

References 46 publications

(74 reference statements)

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“…256 Nox4 is upregulated in pericytes after acute ischemia in peri-infarct areas and enhances BBB leakage by activating NF-κB and MMP9 production. 257 The upregulation of Nox4 is greater in permanent compared to transient focal ischemia, suggesting that ischemia is a strong inducer for Nox4 and subsequent ROS production in pericytes. The increased level of ROS causes detrimental effects in other already compromised cells within the NVU.…”

Section: Part II Neurovascular Injury and Repair After Ischemic Strokementioning

confidence: 97%

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Silva

Chen

et al. 2017

Circulation Research

300

237

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The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury following ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier (BBB) is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in BBB integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.

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Section: Part II Neurovascular Injury and Repair After Ischemic Strokementioning

confidence: 97%

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Silva

Chen

et al. 2017

Circulation Research

300

237

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“…During ischemia, as in SVD, ROS production and MMP9 up-regulation in pericytes contribute to BBB breakdown. An enzymatic source of ROS production, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), is highly up-regulated by pericytes in the peri-infarct region of the mouse brain subjected to middle cerebral artery occlusion (MCAO), and overexpression of NOX4 in pericytes induces BBB breakdown by up-regulating MMP9 (Nishimura et al, 2016). Pericytes also directly release MMP9 during ischemia, which interrupts the tight junctions between endothelial cells and the binding of astrocyte endfeet to the vascular wall (Underly et al, 2017).…”

Section: Cerebral Ischemic Strokementioning

confidence: 99%

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Uemura

Maki

Ihara

et al. 2020

Front. Aging Neurosci.

150

112

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Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid β clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.

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“…Likewise, administration of the NOX inhibitor VAS2870 at 2 and 12 h after tMCAO also reduces ischemic brain injury after focal cerebral ischemia, an effect possibly due to inhibition of NOX4 [140]. Moreover, mice engineered to overexpress NOX4 in brain pericytes had significantly greater infarct volume after focal cerebral ischemia, along with enhanced reactive oxygen species production and blood–brain barrier breakdown in the peri-infarct region [167]. VAS2870 IV treatment in a tMCAO model showed increased expression of microRNAs targeting NOX2 and NOX4, suggesting that the neuroprotective effects of VAS2870 may also be mediated through regulation of microRNAs [168].…”

Section: Introductionmentioning

confidence: 99%

NADPH oxidase in brain injury and neurodegenerative disorders

Merry

Wang

Zhang

et al. 2017

Mol Neurodegeneration

329

309

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Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.

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Detrimental role of pericyte Nox4 in the acute phase of brain ischemia

Cited by 67 publications

References 46 publications

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

NADPH oxidase in brain injury and neurodegenerative disorders

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