Obesity, metabolic syndrome, and diabetes are interrelated conditions that are major risk factors for ischemic stroke. Their effects include endothelial cell (EC) dysfunction, hypertension, cerebral vascular inflammation, and increased thrombosis. In addition to increasing the risk of stroke, these conditions also significantly impact stroke outcomes, increasing the risk of symptomatic intracerebral hemorrhage (sICH), and reducing the efficacy of thrombolysis. This relationship between systemic metabolic disturbances and poor stroke outcomes has been studied for over 40 years; however, the mechanism(s) that lead to poor outcomes and the increased risk of hemorrhagic transformation are still not understood. It is therefore essential to study mechanisms of stroke evolution in models with these comorbidities. To address this compelling problem, we have established two models of ischemic stroke in mice with diet'induced obesity (DIO). DIO is a model of metabolic syndrome/pre-diabetes where the mice develop obesity, hyperinsulinemia, hyperglycemia, and hypertension; and our preliminary studies show that, similar to humans, DIO in mice significantly increases the risk of ICH following thrombolysis with tissue plasminogen activator (tPA). Our long-term goal is to understand the molecular pathways triggered by thrombolytic tPA that increase the risk of ICH and how these pathways are affected by metabolic dysregulation. By targeting these pathways and reducing the risk of sICH it should be possible to make thrombolysis safer and more effective, permitting treatment in more patients. Accordingly, this proposal will test the hypothesis that the reduced effectiveness of tPA treatment and the increased risk of hemorrhagic complications associated with the comorbidities of obesity and pre-diabetes are due in part to upregulation of the signaling pathway controlled by vascular endothelial growth factor-b (VEGF-B) in cerebral endothelial cells. The studies proposed will use state of the art imaging, and in vivo analysis, together with specific unique blocking agents, and genetically modified mice to provide essential mechanistic data necessary to test this hypothesis.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|