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

Publication date: Available online 29 July 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Jia Li, Yang Zhao, Paul Coleman, Jinbiao Chen, Ka Ka Ting, Jaesung Peter Choi, Xiangjian Zheng, Mathew A. Vadas, Jennifer R. GambleAbstractCerebral 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 actin cytoskeleton reorganization, are only exhibited in monolayers of CCM-silenced endothelial cells subjected to low FSS. Our data establishes that shear s...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research