Date of Award

2020

Embargo Period

8-1-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Andy Shih

Second Advisor

Narayan Bhat

Third Advisor

Christopher Cowan

Fourth Advisor

Mark Majesky

Fifth Advisor

Barry Gumbiner

Abstract

Pericytes are mural cells that line the brain’s vast capillary network. In many age-dependent neurological diseases, including Alzheimer’s disease, vascular dysfunction involves early degeneration of pericytes. The brain’s innate mechanism to restore pericyte-endothelial contact, and the consequences of its failure, remain poorly understood. We use in vivo two-photon microscopy in adult and aged mice with genetically labeled pericytes to address this gap in knowledge. We first characterize the structural dynamics of pericytes under basal conditions. We find that while pericyte somata are stable, their terminal processes can occasionally extend and retract over time. Next, by using precise two-photon photothermal ablation, we delete individual pericytes from the living mouse cortical capillary bed. We show that unveiling large stretches of endothelium (~200 to 800 micrometers in total vascular length) through pericyte ablation causes capillary dilation but not blood-brain barrier leakage. Following ablation, neighboring pericytes mount a remodeling response by extending their processes into the uncovered area in the following weeks. In the adult brain, pericyte-endothelial contact and capillary tone is efficiently restored by synergistic growth of processes from numerous neighboring pericytes. In the aged brain, this mechanism is inefficient due to slowed growth of pericytes in capillary and pre- capillary zones, leading to persistent, exacerbated capillary dilation. Dilated capillaries carry higher blood flow and can steal blood from neighboring un-dilated vessels to create mal- distribution and interruption of flow. These findings establish a link between pericyte loss and capillary flow impairment, and highlight pericyte remodeling as target to promote recovery of pericyte-endothelial contact for the re-establishment of capillary tone.

Rights

All rights reserved. Copyright is held by the author.

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