Neves, K. B. , Morris, H., Alves-Lopes, R., Muir, K. W. , Moreton, F., Delles, C. , Montezano, A. C. and Touyz, R. M. (2021) Peripheral arteriopathy caused by Notch3 gain-of-function mutation involves ER and oxidative stress and blunting of NO∕sGC∕cGMP pathway. Clinical Science, 135(6), pp. 753-773. (doi: 10.1042/CS20201412) (PMID:33681964)
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Abstract
Notch3 mutations cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoenephalopathy (CADASIL), which predisposes to stroke and dementia. CADASIL is characterized by vascular dysfunction and granular osmiophilic material (GOM) accumulation in cerebral small vessels. Systemic vessels may also be impacted by Notch3 mutations. However vascular characteristics and pathophysiological processes remain elusive. We investigated mechanisms underlying the peripheral vasculopathy mediated by CADASIL-causing Notch3 gain-of-function mutation. We studied: i) small arteries and vascular smooth muscle cells (VSMC) from TgNotch3R169C mice (CADASIL model), ii) VSMCs from peripheral arteries from CADASIL patients, and iii) post-mortem brains from CADASIL individuals. TgNotch3R169C vessels exhibited GOM deposits, increased vasoreactivity and impaired vasorelaxation. Hypercontractile responses were normalized by fasudil (Rho kinase inhibitor) and 4-PBA (endoplasmic-reticulum (ER) stress inhibitor). Ca2+ transients and Ca2+ channel expression were increased in CADASIL VSMCs, with increased expression of Rho GEFs and ER stress proteins. Vasorelaxation mechanisms were impaired in CADASIL, evidenced by decreased eNOS phosphorylation and reduced cGMP levels, with associated increased guanylate cyclase (sGC) oxidation, decreased sGC activity and reduced levels of the vasodilator H2O2. In VSMCs from CADASIL patients, sGC oxidation was increased and cGMP levels decreased, effects normalized by fasudil and 4-PBA. Cerebral vessels in CADASIL patients exhibited significant oxidative damage. In conclusion, peripheral vascular dysfunction in CADASIL is associated with altered Ca2+ homeostasis, oxidative stress and blunted eNOS/sGC/cGMP signaling, processes involving Rho kinase and ER stress. We identify novel pathways underlying the peripheral arteriopathy induced by Notch3 gain-of-function mutation, phenomena that may also be important in cerebral vessels.
Item Type: | Articles |
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Additional Information: | This study was supported by grants from the British Heart Foundation (BHF) (RE/13/5/30177; 18/6/34217) and the MRC (MC-PC-15076). The CADASIL biopsy samples were funded by grants from The Neurosciences Foundation and The Stroke Association (TSA 2013/02) and the control biopsy samples were funded by grants from the Department of Medicine, University of Ottawa and the Canadian Institutes of Health Research, Canada. RMT is supported through a BHF Chair award (CH/12/29762) and ACM is supported through a Walton Foundation fellowship, University of Glasgow. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Montezano, Dr Augusto and Neves, Dr Karla and Moreton, Dr Fiona and Muir, Professor Keith and Touyz, Professor Rhian and Delles, Professor Christian and Morris, Hannah |
Authors: | Neves, K. B., Morris, H., Alves-Lopes, R., Muir, K. W., Moreton, F., Delles, C., Montezano, A. C., and Touyz, R. M. |
College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
Journal Name: | Clinical Science |
Publisher: | Portland Press |
ISSN: | 0143-5221 |
ISSN (Online): | 1470-8736 |
Published Online: | 08 March 2021 |
Copyright Holders: | Copyright © 2021 The Author(s) |
First Published: | First published in Clinical Science 135(6): 753-773 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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