2024 Theses Doctoral
Mechanisms regulating vascular function after ischemic brain injury
Persistent cerebrovascular dysfunction has been postulated as one mechanism that may contribute to divergent functional trajectories after ischemic stroke. However, how brain endothelial cells (BECs) acutely respond to ischemia and what endogenous signals subsequently regulate vascular normalization remain poorly understood.
To spatiotemporally interrogate neuronal activity and hemodynamics in the acute period after ischemic brain injury we used wide-field imaging. Local ischemia consistently provoked a large-amplitude cortical spreading depolarization (CSD) accompanied by strong vasoconstriction, followed by subsequent diverse CSDs with varying hemodynamic responses. Small CSDs with slow depolarization induced vasodilation in well oxygenated cortical tissue. CSDs of larger amplitude with non-sustained depolarization induced biphasic vascular responses. CSDs of large amplitude, characterized by rapid and prolonged depolarization, drove vasoconstriction in deoxygenated cortical tissue with sustained neuronal depolarization. These observations support a model in which vascular responses after acute brain injury are dependent upon the local relationship between CSD features (i.e. slope, duration, and amplitude of depolarization) and the underlying cortical state (i.e. neuronal activity, perfusion, oxygenation).
After this acute period, the ischemic brain is characterized by profound changes in immune cell composition and function. To understand how distinct immune signaling pathways regulate blood-brain barrier (BBB) repair and vascular remodeling after ischemic brain injury, I investigated a unique post-ischemic BEC type one interferon (IFN1) signature. Functional assays and single-cell transcriptomic analyses in IFN1 receptor (Ifnar1) inducible EC knockout (iECKO) mice revealed that loss of BEC IFN1 signaling exacerbated post-stroke barrier disruption and resulted in an expansion of BECs enriched in genes involved in angiogenic processes. Conversely, acute administration of exogenous IFNI ameliorated post stroke BBB disruption. In vitro assays supported that IFNI signaling modulates BEC junctional protein stabilization and vascular endothelial growth factor (VEGF) signaling to enhance BEC barrier properties and suppress angiogenic features, respectively. These findings suggest that endogenous BEC IFN signaling after ischemic brain injury restricts angiogenesis to potentially promote acute barrier function.
These studies, which span from the systems to molecular level, demonstrate that brain ischemia and post-ischemic sequelae have a profound impact on cerebrovascular dysfunction and recovery. Furthermore, each study introduces a novel framework to investigate how differences in acute BEC responses may contribute to variable vascular trajectories and longitudinal brain function after ischemic insult.
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More About This Work
- Academic Units
- Neurobiology and Behavior
- Thesis Advisors
- Agalliu, Dritan
- Degree
- Ph.D., Columbia University
- Published Here
- January 15, 2025