Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease

Pokhilko, A. et al. (2021) Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease. Journal of Cerebral Blood Flow and Metabolism, 41(9), pp. 2423-2438. (doi: 10.1177/0271678X211004307) (PMID:33730931)

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The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.

Item Type:Articles
Additional Information:This research reported in this publication was primarily supported by a Stroke Association priority programme award in Advancing Care and Treatment of Vascular Dementia (grant reference number 16VAD_04) in partnership with the British Heart Foundation and Alzheimer's Society. KH received funding support from the Alzheimer’s Society (152 (PG-157); 290 (AS-PG-15b-018); 228 (AS-DTC-2014-017)) and Alzheimer’s Research UK (ARUK) (ARUK-PG2016B-6). TVA was funded by MRC (MR/R005567-1), BHF (PG/15/92/31813), Stroke Association (PPA 2016/02) and Heart Research UK (RG 2664/17/20). SS was also funded by BHF Fellowship (FS/18/46/33663) and the Cambridge BHF Centre for Research Excellence. SMA was funded by MRC, BHF and Leducq Foundation.
Glasgow Author(s) Enlighten ID:Pokhilko, Dr Alexandra and Brezzo, Dr Gaia and Van Agtmael, Professor Tom
Authors: Pokhilko, A., Brezzo, G., Handunnetthi, L., Heilig, R., Lennon, R., Smith, C., Allan, S. M., Granata, A., Sinha, S., Wang, T., Markus, H. S., Naba, A., Fischer, R., Van Agtmael, T., Horsburgh, K., and Cader, M. Z.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Journal of Cerebral Blood Flow and Metabolism
Publisher:SAGE Publications
ISSN (Online):1559-7016
Published Online:17 March 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Journal of Cerebral Blood Flow and Metabolism 41(9): 2423-2438
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172813Targeting intracellular pathways to dissect mechanisms of cerebrovascular disease.Tom Van AgtmaelBritish Heart Foundation (BHF)PG/15/92/31813Institute of Cardiovascular & Medical Sciences