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

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Jia LiJennifer R Gamble

Abstract

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 previou...Continue Reading

Citations

Oct 20, 2020·Frontiers in Cell and Developmental Biology·Yizhe Zhang, Xiao Yang
Sep 3, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Concetta ScimoneAntonina Sidoti
Dec 6, 2020·Communications Biology·Amber N StratmanBrant M Weinstein
Jul 2, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Zahra Alvandi, Joyce Bischoff
Sep 25, 2021·Journal of Magnetic Resonance Imaging : JMRI·Je Yeong SoneIssam A Awad
May 28, 2021·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Je Yeong SoneIssam A Awad

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