Little is known about intracranial aneurysm (IA) formation. We submit that specific hemodynamic conditions, not evaluated in prior aneurysm models, are critical for IA formation. Using a rabbit IA model, this project seeks to define these specific hemodynamic conditions responsible for aneurysm initiation and to identify key molecular responses in the pathological vascular remodeling that initiates aneurysms. We hypothesize that: 1) unusual hemodynamics at cerebrovascular bifurcations that is characterized by high wall shear stress (WSS) and wall shear stress gradient (WSSG) induces aneurysmal destructive remodeling, and 2) this pathological response is mediated by localized hemodynamic stimulation of nitric oxide (NO) production and matrix metalloproteinase (MMP) activity. We will evaluate the dose-dependence of this hemodynamic initiation of IAs and use computational fluid dynamics (CFD) to map the initiating hemodynamics. This will define the specific hemodynamic conditions responsible for inducing BT aneurysms, and allow subsequent experiments to examine the biological responses to IA-initiating hemodynamics that precede aneurysm formation. We will then examine hemodynamically induced changes in nitric oxide production and MMP activity during this early period of aneurysm initiation. The roles of NO and MMP in hemodynamic induction of IAs will be tested via pharmacological manipulation of these molecules.
Aim 1. Determine specific hemodynamic conditions responsible for flow-induced IA initiation.
Aim 2. Determine the role of MMPs in hemodynamic initiation of IAs.
Aim 3. Determine the role of iNOS in regulating hemodynamic initiation of IAs. Significance: IA rupture is associated with devastating consequences for patients with high mortality and morbidity. IA formation remains poorly understood. Elucidating the role of specific hemodynamics in IA initiation will pave the way for new mechanistic understandings of IA growth and possibly rupture.
Intracranial aneurysms have catastrophic consequences with high morbidity and mortality if they rupture. What causes intracranial aneurysms to develop is unclear, but blood flow (hemodynamics) conditions play an important role. This study seeks to elucidate the specific hemodynamic and biological mechanisms involved in initiating intracranial aneurysms in order to pave the way for improved diagnostic and prognostic capabilities and the development of more effective prevention strategies and less invasive therapies.
|Xiang, Jianping; Varble, Nicole; Davies, Jason M et al. (2017) Initial Clinical Experience with AView-A Clinical Computational Platform for Intracranial Aneurysm Morphology, Hemodynamics, and Treatment Management. World Neurosurg 108:534-542|
|Mokin, Maxim; Setlur Nagesh, Swetadri Vasan; Ionita, Ciprian N et al. (2016) Stent retriever thrombectomy with the Cover accessory device versus proximal protection with a balloon guide catheter: in vitro stroke model comparison. J Neurointerv Surg 8:413-7|
|Tutino, Vincent Matthew; Liaw, Nicholas; Spernyak, Joseph Andrew et al. (2016) Assessment of Vascular Geometry for Bilateral Carotid Artery Ligation to Induce Early Basilar Terminus Aneurysmal Remodeling in Rats. Curr Neurovasc Res 13:82-92|
|Mokin, Maxim; Kan, Peter; Sivakanthan, Sananthan et al. (2016) Endovascular therapy of wake-up strokes in the modern era of stent retriever thrombectomy. J Neurointerv Surg 8:240-3|
|Brouillard, Adam M; Sun, Xingwen; Siddiqui, Adnan H et al. (2016) The Use of Flow Diversion for the Treatment of Intracranial Aneurysms: Expansion of Indications. Cureus 8:e472|
|Lin, Ning; Brouillard, Adam M; Mokin, Maxim et al. (2015) Direct access to the middle meningeal artery for embolization of complex dural arteriovenous fistula: a hybrid treatment approach. J Neurointerv Surg 7:e24|
|Shakir, Hakeem J; Diletti, Sara M; Hart, Alexandra M et al. (2015) Carotid body tumor imitator: An interesting case of Castleman's disease. Surg Neurol Int 6:181|
|Xiang, Jianping; Yu, Jihnhee; Choi, Hoon et al. (2015) Rupture Resemblance Score (RRS): toward risk stratification of unruptured intracranial aneurysms using hemodynamic-morphological discriminants. J Neurointerv Surg 7:490-5|
|Lin, Ning; Wong, Andrew K; Lipinski, Lindsay J et al. (2015) Reversible changes in diffusion- and perfusion-based imaging in cerebral venous sinus thrombosis. BMJ Case Rep 2015:|
|Tutino, Vincent M; Mandelbaum, Max; Takahashi, Akira et al. (2015) Hypertension and Estrogen Deficiency Augment Aneurysmal Remodeling in the Rabbit Circle of Willis in Response to Carotid Ligation. Anat Rec (Hoboken) 298:1903-10|
Showing the most recent 10 out of 73 publications