Hemodynamics induced intracranial aneurysm initiation: Mechanism and model exploration
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Understanding the molecular mechanisms of intracranial aneurysms (IAs) is paramount to developing treatment strategies for preventing IA initiation and growth, and to understanding why some IAs are asymptomatic while others rupture with devastating consequences. Unique hemodynamics, specifically high wall shear stress (WSS) and positive wall shear stress gradient (WSSG) play a critical role in IA initiation, and so the molecular mechanism subsequent to hemodynamic mechanotransduction is an important gap in understanding IAs. A hemodynamics induced rabbit IA model was used to determine if high WSS and positive WSSG affects endothelial nitric oxide synthase (eNOS) expression/activity, and if eNOS-derived nitric oxide (NO) or superoxide leads to smooth muscle cell (SMC) production of matrix metalloproteinases (MMPs) and IA initiation. Results showed that eNOS production of NO in the intima and superoxide production in the media independently led to IA initiation. Both eNOS and superoxide caused IA damage in part via SMC de-differentiation and MMP2/9 production. To expand the available tools for studying hemodynamics driven IA mechanisms, the rabbit bilateral common carotid artery ligation model was attempted in a novel rat model. While successful computational fluid dynamics demonstrated increased WSS and WSSG after ligation in the rat, IAs fail to form in the rat BT compared to the rabbit given the same treatment. Allometric scaling can potentially be used to compare biological findings across species, as well as to estimate biological values not otherwise obtainable. The feasibility of allometric scaling was assessed for estimating the WSS and WSSG thresholds for IA initiation in humans based on rabbit model threshold data and other available animal data. Scaling agreed well between rabbit and human, and an estimated threshold predicted that rats would not form IAs in the bilateral common carotid artery ligation model based on WSS and WSSG data. In sum, this work both contributed to understanding the mechanism of hemodynamics induced IA initiation as well as facilitated its study in the future.