All ETDs from UAB

Advisory Committee Chair

Harald Sontheimer

Advisory Committee Members

Lori L McMahon

Mark O Bevensee

Kent Keyser

Lucas Pozzo-Miller

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cerebral blood flow is regulated by vasoactive molecules released by astroglial cell processes that ensheath the entire cerebrovasculature. This regulation of blood flow in response to neuronal activity is a process known as functional hyperemia. Astrocytes, along with their associated neurons and microvessels, are organized into a functional system called the gliovascular unit (GVU). The astroglial component of the GVU is integral in both regulation of blood flow and maintenance of the blood-brain barrier (BBB). In disease, this system can be disrupted. We found that glioma cells displace astrocytic processes, called endfeet, and prevent their communication with associated vessels, leading to a loss of astrocyte-vascular regulation. In addition to this disruption of gliovascular coupling, vessel associated glioma cells demonstrate the ability to co-opt vascular regulation, likely for their own biological advantage. Similarly, vascular amyloid in Alzheimer disease displaces astrocytic endfeet and disrupts astrocyte-vascular regulation; however, unlike in the glioma model, the effect is primarily due to diminished iv vessel responsiveness. Furthermore, vascular amyloid does not demonstrate vascular cooption, as do the glioma cells. Most neurological diseases present with neurovascular dysfunction yet, surprisingly, very little is currently understood about the contribution of GVU pathology. Understanding how disruption of gliovascular coupling contributes to, or results from, disease will further enhance our ability to develop novel, effective treatments for neurological diseases.

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