Abnormal vascular remodeling triggered by hemodynamic stresses on blood vessels is believed to be one of the key processes in the development and rupture of intracranial aneurysms. However, mechanisms linking hemodynamic stresses to the development and rupture of intracranial aneurysms are not well understood. Inflammatory cells are emerging as a key mediator for angiogenesis and vascular remodeling. Our general hypotheses are (1) inflammatory cells are key mediators for flow-induced outward vascular remodeling and (2) intracranial aneurysms, a model of abnormal remodeling, result from excessive hemodynamically- induced vascular remodeling mediated by inflammatory cells.
Aim 1. Critical roles of neutrophils and macrophages in flow-induced adaptive outward vascular remodeling. Using a rodent common carotid artery flow augmentation model, we will demonstrate that depletion of neutrophils and/or macrophages reduces flow-induced outward vascular remodeling and matrix metalloproteinases (MMPs) in the vascular wall.
Aim 2. Critical roles of MMPs in flow-induced adaptive outward vascular remodeling. We will demonstrate critical roles of MMP-9 and MMP-2 in normal flow- induced remodeling using pharmacological and genetic approaches coupled with bone marrow transplant.
Aim 3. Critical roles of inflammatory cells and MMPs in intracranial aneurysm formation -long-term flow- induced maladaptive vascular remodeling. Using a rodent aneurysm model, we will demonstrate that depletion of neutrophils and/or macrophages decreases the incidence of intracranial aneurysms and that MMP-9 and MMP-2 knockout mice demonstrate reduced incidence of aneurysm formation compared to the wild type mice. Relevance. Elucidating the roles of inflammatory cells in normal vascular remodeling and abnormal vascular remodeling-intracranial aneurysm formation- will be the basis for future studies to develop new therapeutic targets to slow or prevent aneurysmal growth and rupture. The management of unruptured intracranial aneurysms still remains controversial. In some patients, the risks of surgical treatment may be higher than a risk of rupture. New treatments targeting vascular remodeling and inflammation through inhibition of MMPs or other cytokines could potentially benefit this subset of patients.
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