Date of Award

Spring 2-24-2025

Embargo Period

3-11-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology and Laboratory Medicine

Additional Department

Molecular and Cellular Biology and Biopathology

College

College of Graduate Studies

First Advisor

William Hill

Second Advisor

Adviye Ergul

Third Advisor

Hongkuan Fan

Fourth Advisor

Meng Liu

Fifth Advisor

Robin Muise-Helmericks

Abstract

Diabetes increases the risk of stroke and Vascular Contributions to Cognitive Impairment and Dementia (VCID). Diabetes also dysregulates the endothelin (ET) system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. However, there is a loss of BMVPCs in VCID, but underlying mechanisms of pericyte degeneration are poorly studied. ETA receptor activation can instigate phenotypical changes and cellular senescence in endothelial cells. . There is also emerging evidence that ETB receptor agonism improves outcomes in patients with cerebral ischemic stroke, but long-term effects, especially in diabetes, are unknown. Therefore, this study aimed to determine if pericyte degeneration and phenotypical changes contribute to progressive VCID in an ET-1-dependent manner under diabetic conditions. For in vitro studies, human male BMVPCs were grown in diabetes-like and oxidative stress conditions. BMVPCs were treated with ET-1 to determine its effects on senescence and phenotype. For in vivo studies, we used a post-stroke cognitive impairment (PSCI) model of VCID to test the effects of inhibition of ETA with BQ-123 or stimulation of ETB with Sovateltide via intranasal administration on cognitive outcomes. In vitro studies confirmed that ET-1 increased β-galactosidase activity which was prevented by BQ-123. ET-1 also increased traditional and pericyte-specific senescence markers. Furthermore, ET-1 stimulated a shift toward an ensheathing or microglia-like pericyte phenotype. Our in vivo studies demonstrated that Sovateltide and BQ-123 improved multiple cognitive domains. Both Sovateltide and BQ-123 improved VCID plasma markers after stroke. Pericytes also displayed phenotypic changes in diabetes after stroke, but these pathological shifts were reduced with BQ-123 and Sovateltide. In conclusion, our findings support the idea that diabetes triggers ET-1-induced senescence and causes phenotypical changes in BMVPCs. Additionally, our results suggest that intranasal stimulation of brain ETB receptors or ETA receptor inhibition can prevent cognitive decline after stroke. While further studies are required to better understand how the brain ET system impacts stroke recovery in diabetes, our findings provide novel insights into potential neurovascular protective therapies for VCID.

Rights

Copyright is held by the author. All rights reserved.

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