Optimization and Translational Validation of a Novel Mouse Surgical Model of Moyamoya Syndrome

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Description

Abstract Moyamoya is a cerebrovascular condition in which the terminal ICA and its major branches undergo progres- sive stenosis, leading to reduced blood flow to the brain. As a compensatory mechanism, an abnormal vascular network of collateral arteries develop at the base of the brain within the lenticulostriate region. Symptoms include hemorrhagic stroke, ischemic stroke, headache, transient ischemic attack, seizures, and cognitive impairment. The small, tortuous arteries that develop in response to ischemia branch off the circle of Willis and are prone to rupture, causing an intracranial hemorrhage, a major risk factor for morbidity and mortality of moyamoya patients. The precise pathophysiology that leads to hemorrhage is not fully understood, but hemodynamic stress and inflammation are thought to play an important role. We have worked to optimize the internal carotid artery ste- nosis (ICAS) surgical method in mice to investigate the pathological changes that occur following stenosis. We observe a significant decrease in diameter of the intracranial ICA, vascular wall thickening, vessel disruption in the cortical watershed region, blood-brain barrier (BBB) permeability, neuroinflammation and the presence of microbleeds. What is not known is how the effects of vessel stenosis prior to a large hemorrhagic event affect post-hemorrhage recovery and risk of rebleeding. Therefore, we propose a continuation of our studies, with a focus on neuroinflammation, BBB dysfunction, and cerebrovascular anatomical alterations. We hypothesize that ICAS induces a cycle of pathology that includes chronic inflammation and vascular instability, which predisposes blood vessels to an increased risk of bleeding. To test this hypothesis, we will combine our ICAS mouse model with a model of intracerebral hemorrhage (ICH) and 1) define the inflammatory mechanisms that contribute to intracranial bleeding, 2) identify the BBB permeability mechanisms that contribute to intracranial bleeding, and 3) quantify the anatomical cerebrovascular alterations that occur following ICAS and ICH in mice using microCT imaging. We anticipate ICAS will sensitize the animals to experience an increased ICH-induced hematoma vol- ume due, in part, to an increase in T cell expression, increased BBB permeability from MMP-9 activity, and alterations in the lenticulostriate arteries, all of which make the tissue vulnerable to future bleeding events. In addition to our animal studies, we will continue to enroll patients into our Moyamoya and Stroke Tissue and Evaluation Repository (MASTER) study to increase our knowledge about what inflammatory and vessel-related changes are occurring in our local moyamoya syndrome patient population.
StatusFinished
Effective start/end date7/30/216/30/22

Funding

  • National Center for Advancing Translational Sciences

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