Low fluid shear stress conditions contribute to activation of cerebral cavernous malformation signalling pathways

Low fluid shear stress conditions contribute to activation of cerebral cavernous malformation signalling pathways.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.bbadis.2019.07.013
Journal or Publication Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Volume: 1865
Number: 11
Page Range: p. 165519
Date: 2019
Divisions: Cell Signalling
Vascular Biology
Depositing User: General Admin
Identification Number: 10.1016/j.bbadis.2019.07.013
ISSN: 09254439
Date Deposited: 21 Dec 2020 23:25

Cerebral cavernous malformations (CCMs) are vascular malformations that cause hemorrhagic stroke. CCMs can arise from loss-of-function mutations in any one of CCM1 (KRIT1), CCM2 or CCM3 (PDCD10). Despite the mutation being in all endothelial cells the CCM lesions develop primarily in the regions with low fluid shear stress (FSS). Here we investigated the role of FSS in the signalling pathways associated with loss of function of CCM genes. We performed transcriptomic analysis on CCM1 or CCM2-silenced endothelial cells subjected to various FSS. The results showed 1382 genes were deregulated under low FSS, whereas only 29 genes were deregulated under high FSS. Key CCM downstream signalling pathways, including increased KLF2/4 expression, actin cytoskeleton reorganization, TGF-β and toll-like receptor signalling pathways and also oxidative stress pathways, were all highly upregulated but only under low FSS. We also show that the key known phenotypes of CCM lesions such as disrupted endothelial cell junction, increased inflammatory response/oxidative stress and elevated RhoA-ROCK activity, are only exhibited in monolayers of CCM-silenced endothelial cells subjected to low FSS. Our data establishes that shear stress acts as a previously unappreciated but important regulator for CCM gene function and may determine the site of CCM lesion development.

Keywords: Cerebral cavernous malformations; Endothelial cells; Fluid hear stress; Inflammation; RNA sequencing.

Copyright © 2019. Published by Elsevier B.V.

Li, Jia
Zhao, Yang
Coleman, Paul
Chen, Jinbiao
Ting, Ka Ka
Choi, Jaesung Peter
Zheng, Xiangjian
Vadas, Mathew A.
Gamble, Jennifer R.
Last Modified: 21 Dec 2020 23:25
URI: https://eprints.centenary.org.au/id/eprint/138

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