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PRELP secreted from mural cells protects the function of blood brain barrier through regulation of endothelial cell-cell integrity

Davaapil, H; Hopkins, J; Bonnin, N; Papadaki, V; Leung, A; Kosuge, H; Tashima, T; ... Ohnuma, SI; + view all (2023) PRELP secreted from mural cells protects the function of blood brain barrier through regulation of endothelial cell-cell integrity. Frontiers in Cell and Developmental Biology , 11 , Article 1147625. 10.3389/fcell.2023.1147625. Green open access

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Abstract

INTRODUCTION: Proline/arginine-rich end leucine-rich repeat protein (PRELP), is a small secreted proteoglycan expressed by pericytes and vascular smooth muscle cells surrounding the brain vasculature of adult mouse. METHODS: We utilised a Prelp knockout (Prelp−/−) mouse model to interrogate vasculature integrity in the brain alongside performing in vitro assays to characterise PRELP application to endothelial cells lines. Our findings were supplemented with RNA expression profiling to elucidate the mechanism of how PRELP maintains neurovasculature function. RESULTS: Prelp−/− mice presented with neuroinflammation and reducedneurovasculature integrity, resulting in IgG and dextran leakage in the cerebellum and cortex. Histological analysis of Prelp−/− mice revealed reducedcell-cell integrity of the blood brain barrier, capillary attachment of pericytes andastrocyte end-feet. RNA-sequencing analysis found that cell-cell adhesion andinflammation are affected in Prelp−/− mice and gene ontology analysis as well as gene set enrichment analysis demonstrated that inflammation related processes and adhesion related processes such as epithelial-mesenchymal transition and apical junctions were significantly affected, suggesting PRELP is a regulator of cell-cell adhesion. Immunofluorescence analysis showed that adhesion junction protein expression levels of cadherin, claudin-5, and ZO-1, was suppressed in Prelp−/− mice neurovasculature. Additionally, in vitro studies revealed that PRELP application to endothelial cells enhances cell-cell integrity, induces mesenchymal-endothelial transition and inhibits TGF-β mediated damage to cell-cell adhesion. DISCUSSION: Our study indicates that PRELP is a novel endogenous secreted regulator of neurovasculature integrity and that PRELP application may be a potential treatment for diseases associated with neurovascular damage.

Type: Article
Title: PRELP secreted from mural cells protects the function of blood brain barrier through regulation of endothelial cell-cell integrity
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fcell.2023.1147625
Publisher version: https://doi.org/10.3389/fcell.2023.1147625
Language: English
Additional information: © 2023 Davaapil, Hopkins, Bonnin, Papadaki, Leung, Kosuge, Tashima, Nakakido, Sekido, Tsumoto, Sagoo and Ohnuma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: BBB, EndMT, PRELP, adhesion, integrity, neuroinflammation, vasculature
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10181979
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