Abstract
IntroductionEnlargement of a pre-existing intracranial aneurysm is a well-established risk factor of rupture. Excessive low wall shear stress concomitant with turbulent flow in the dome of an aneurysm may contribute to progression and rupture. However, how stress conditions regulate enlargement of a pre-existing aneurysm remains to be elucidated.ResultsWall shear stress was calculated with 3D-computational fluid dynamics simulation using three cases of unruptured intracranial aneurysm. The resulting value, 0.017 Pa at the dome, was much lower than that in the parent artery. We loaded wall shear stress corresponding to the value and also turbulent flow to the primary culture of endothelial cells. We then obtained gene expression profiles by RNA sequence analysis. RNA sequence analysis detected hundreds of differentially expressed genes among groups. Gene ontology and pathway analysis identified signaling related with cell division/proliferation as overrepresented in the low wall shear stress–loaded group, which was further augmented by the addition of turbulent flow. Moreover, expression of some chemoattractants for inflammatory cells, including MCP-1, was upregulated under low wall shear stress with concomitant turbulent flow. We further examined the temporal sequence of expressions of factors identified in an in vitro study using a rat model. No proliferative cells were detected, but MCP-1 expression was induced and sustained in the endothelial cell layer.ConclusionsLow wall shear stress concomitant with turbulent flow contributes to sustained expression of MCP-1 in endothelial cells and presumably plays a role in facilitating macrophage infiltration and exacerbating inflammation, which leads to enlargement or rupture.
Highlights
Enlargement of a pre-existing intracranial aneurysm is a well-established risk factor of rupture
Change of gene expression profile To verify the effect of each wall shear stress (WSS) on gene expression, a primary culture of endothelial cell (EC) from human carotid artery was cultured and shear stress corresponding to the value (3.0 Pa, 0.05 Pa) obtained in Computational fluid dynamic (CFD) was loaded on these cells for 24 h
Because some studies have demonstrated the presence of turbulent flow in addition to low WSS at the rupture point of Intracranial aneurysm (IA) in human cases [14, 15], cultured ECs were loaded with the turbulent flow in combination with low WSS
Summary
Enlargement of a pre-existing intracranial aneurysm is a well-established risk factor of rupture. Excessive low wall shear stress concomitant with turbulent flow in the dome of an aneurysm may contribute to progression and rupture. Subarachnoid hemorrhage often causes sudden death without a chance for therapeutic intervention, even in young patients, and its prognosis is still quite poor regardless of improvements in Experimental studies using an animal model of IA have clarified the crucial role of persistent inflammation, presumably triggered by high wall shear stress (WSS). Considered with the fact that the target of treatment is preexisting IAs and that a recent cohort study in Japan clearly demonstrated the positive correlation of the size of IAs with the annual risk of rupture [17], factors induced in ECs under low WSS condition may be good candidates for development of therapeutic drugs to prevent enlargement and presumably rupture of pre-existing IAs
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