ER stress and Rho kinase activation underlie the vasculopathy of CADASIL

Neves, Karla B; Harvey, Adam; Moreton, Fiona; Montezano, Augusto C.; Alves-Lopes, Rhéure; Cat, Aurélie Nguyen Dinh; Rocchicciolli, Paul; Delles, Christian; Joutel, Anne; Muir, Keith W.; Touyz, Rhian M.

doi:10.1172/jci.insight.131344

Cited by 41 publications

(29 citation statements)

References 61 publications

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“…Rho kinase activity and ER stress were linked to changes in VSMC morphology but not to proliferative responses to Notch3. This human study was further supported by data showing Notch3 activation in the transgenic Notch3R169C mouse CADASIL model [105].…”

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Subsupporting

confidence: 62%

“…A recently published study further complicates the interpretation of the CADASIL phenotype and provides an alternative explanation [105]. An examination of VSMC primary cultures isolated from CADASIL patients identified increased Notch3 signalling was identified through quantification of Notch3 downstream target HEYL, which was suppressed by gamma-secretase inhibitors.…”

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Submentioning

confidence: 99%

“…This increase was abolished by gamma-secretase inhibitors. The intermediate between ER stress and Notch3 appears to be Notch3-driven expression of NADPH oxidase 5 (Nox5), which regulates the production of reactive oxygen species (ROS) [105]. Rho kinase activity and ER stress were linked to changes in VSMC morphology but not to proliferative responses to Notch3.…”

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Submentioning

confidence: 99%

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Notch3 in Development, Health and Disease

Hosseini-Alghaderi

Baron

2020

Biomolecules

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Notch3 is one of four mammalian Notch proteins, which act as signalling receptors to control cell fate in many developmental and adult tissue contexts. Notch signalling continues to be important in the adult organism for tissue maintenance and renewal and mis-regulation of Notch is involved in many diseases. Genetic studies have shown that Notch3 gene knockouts are viable and have limited developmental defects, focussed mostly on defects in the arterial smooth muscle cell lineage. Additional studies have revealed overlapping roles for Notch3 with other Notch proteins, which widen the range of developmental functions. In the adult, Notch3, in collaboration with other Notch proteins, is involved in stem cell regulation in different tissues in stem cell regulation in different tissues, and it also controls the plasticity of the vascular smooth muscle phenotype involved in arterial vessel remodelling. Overexpression, gene amplification and mis-activation of Notch3 are associated with different cancers, in particular triple negative breast cancer and ovarian cancer. Mutations of Notch3 are associated with a dominantly inherited disease CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and there is further evidence linking Notch3 misregulation to hypertensive disease. Here we discuss the distinctive roles of Notch3 in development, health and disease, different views as to the underlying mechanisms of its activation and misregulation in different contexts and potential for therapeutic intervention.

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Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Subsupporting

confidence: 62%

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Submentioning

confidence: 99%

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Submentioning

confidence: 99%

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Notch3 in Development, Health and Disease

Hosseini-Alghaderi

Baron

2020

Biomolecules

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“…Impaired clearance of the mutated NOTCH3 extracellular domain appears to lead to toxic protein aggregation, cellular damage and degeneration of small cerebral vessels and pericytes [11,12]. This is associated with vascular dysfunction [13,14] that precedes histological evidence of brain damage in mouse models [12] In a cross-sectional study in subjects with CADASIL, we showed that impaired cerebral and peripheral vasoreactivity were associated with higher numbers of lacunes [15]. If changes in vascular function occur early, are pathophysiologically relevant and are amenable to interventions, this may make them excellent biomarkers [12].…”

Section: Introductionmentioning

confidence: 99%

Brain imaging factors associated with progression of subcortical hyperintensities in CADASIL over 2‐year follow‐up

Moreton

Cullen

Dickie

et al. 2020

Euro J of Neurology

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Background and purpose: Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability that is incompletely explained. Early abnormalities in vascular function have been shown in animal models. We postulated that studying changes in vascular function may offer insights into disease progression. Methods: Twenty-two subjects with CADASIL [50% female, 50 (AE11) years] from 19 pedigrees were included in a longitudinal multimodality study using brain magnetic resonance imaging (MRI), clinical measures, neuropsychology and measures of peripheral vascular function. MRI studies included measurement of structural brain changes, cerebral blood flow (CBF) and cerebrovascular reactivity by arterial spin labelling and a CO 2 respiratory challenge. Results: Over 2 years, new stroke or transient ischaemic attack (TIA) occurred in five (23%) subjects and new significant disability in one (5%). There were significant increases in number of lacunes, subcortical hyperintensity volume and microbleeds, and a decrease in brain volume. CBF declined by 3.2 (AE4.5) ml/100 g/min over 2 years. CBF and carotid-femoral pulse wave velocity at baseline predicted change in subcortical hyperintensity volume at follow-up. Carotid intima-media thickness and age predicted brain atrophy. Baseline CBF was lower in subjects who showed a decline in attention and working memory. Conclusions: Cerebral blood flow predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADA-SIL. Over 2 years, there were changes in several relevant imaging biomarkers (CBF, brain volume, lacunes, microbleeds and hyperintensity volume). Future studies in CADASIL should consider assessment of CBF as prognostic factor.

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“…However, it is not fully understood. It is thought that this protein aggregation could lead to a toxic gain of function, as seems to occur with TIMP3 and vitronectin, proteins associated with vessel extracellular matrix (8,9), or even interfere with autophagy (10) or cause endoplasmic reticulum stress (11). Likewise, a proteomic study highlighted the differential protein levels between CADASIL patients and controls regarding extracellular matrix and mitochondrial proteins (12).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide Transcriptome Study in Skin Biopsies Reveals an Association of E2F4 With Cadasil and Cognitive Impairment

Muiño

Maisterra²,

Jiménez-Baladó

et al. 2020

Preprint

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Background:CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the receptor, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, as executive function is characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further.Methods:Agenome-wide transcriptome study(four casespaired with three healthysiblings)was carried out,in addition toa qRT-PCR for validation purposes(ten new cases and eight new controls).Neuropsychological tests were performedto evaluateverbal memory, attention and information processing speed (IPS), motor speed and dexterity, executive function and visuoconstructional skills. The Single-nuclei Brain RNA-seq expression browser (SNBREB) and the GTExPortalwere used to study brain expressionof the significant mRNAs found.Results: The two most significant differentially expressed mRNAs (BANP,p-value=7.23x10-4 and PDCD6IP, p-value=8.36x10-4) were selected for the validation study by qRT-PCR. Additionally, we selectedtwo more mRNAs(CAMK2G,p-value=4.52x10-3 and E2F4, p-value=4.77x10-3) due to their association with ischemic neuronal death. E2F4showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p=1.23x10-3), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expressionwas associated with worseexecutive function (p=2.04x10-2) and attention and IPS (p=8.73x10-2).In silico studies indicated that E2F4 is expressed in brain endothelial cells. Conclusions:Skin biopsies of CADASIL patients presented higher mRNA levels of E2F4and these higher levels have a significant correlation with worseexecutive function and IPS.

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ER stress and Rho kinase activation underlie the vasculopathy of CADASIL

Cited by 41 publications

References 61 publications

Notch3 in Development, Health and Disease

Notch3 in Development, Health and Disease

Brain imaging factors associated with progression of subcortical hyperintensities in CADASIL over 2‐year follow‐up

Genome-wide Transcriptome Study in Skin Biopsies Reveals an Association of E2F4 With Cadasil and Cognitive Impairment

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