The Role of Smooth Muscle Cells in a Rabbit Model of Hemodynamic Intracranial Aneurysm Initiation
Mandelbaum, Max Ruben
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Intracranial aneurysm (IA) is a complex disease which causes sub arachnoid hemorrhage with devastating consequences. There are many risk factors for IA, but hemodynamic forces play a unique role. In order to better understand the role of hemodynamics in IA initiation, a basilar terminus (BT) aneurysm model using bilateral common carotid artery (CCA) ligation in rabbits was utilized to determine the initial aneurysmogenic responses to hemodynamic insult in cerebral arteries. In particular, we undertook this research to understand the role of smooth muscle cells (SMCs) in IA initiation. In studying SMCs, their synthesis of MMP-2 and MMP-9 was shown to be responsible for damage to the extra-cellular. Additionally, these SMCs were shown to be displaying a unique inflammatory phenotype in developing aneurysmal lesions. We sought to better understand the nature of the hemodynamic insult created by bilateral (CCA) ligation at the basilar terminus (BT) where aneurysmal damage is seen. Through longitudinal computation fluid dynamics (CFD) peformed on animals we demonstrated a strong correlation between this hemodynamic insult and IA formation 24 weeks after surgery. Preliminary work was also conducted in order to determine the role of inducible nitric oxide synthase (iNOS) in IA initiation using aminoguanidine, a specific inhibitor of iNOS. However, several shortcomings in this study led to an inability to make any conclusion about whether or not iNOS plays a role in this process. Work was also done to characterize the effects of the flow insult created by bilateral CCA ligation on the entire Circle of Willis to see if IAs would form principally at the BT, or were also occurring elsewhere. Additionally, in order to see if the addition of extra risk factors to the very strong hemodynamic insult, created by bilateral CCA ligation, would cause additional damage, hypertension and estrogen deficiency were added to the model. This work has helped to provide new insight into the initial biological response of the vasculature to aneurysmogenic flow, providing future areas of interest for study in IA biology.