Publication Date

2016-12-08

Availability

Open access

Embargo Period

2016-12-08

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2016-10-11

First Committee Member

Daniel J. Liebl

Second Committee Member

Jae Lee

Third Committee Member

Abigail Hackam

Fourth Committee Member

Kevin K. Park

Fifth Committee Member

Jeffery A. Plunkett

Abstract

Traumatic brain injury (TBI) continues to be a major health concern worldwide. One of the earliest and most profound deficits comes from vascular damage and breakdown of the blood-brain barrier (BBB). Despite the consequences of blood vessel destruction, little is known of the cellular responses that occur in vessel integrity following TBI. B class ephrins and Eph receptors are membrane bound proteins that initiate bidirectional signals during cell-cell interactions, and are indispensable for developmental and pathological neovascularization. The role of EphB3 and its ligand ephrinB3 was investigated in vascular integrity in a murine controlled cortical impact (CCI) injury model of TBI. We identified a novel pro-apoptotic role for EphB3 in cerebral vascular endothelial cells (cvECs) that lead to increased BBB permeability and immune cell infiltration after CCI injury. In addition, EphB3 also regulated the degree of cvECastrocytic end-feet membrane association in the gliovascular unit, as well as the expression of the endothelial intercellular junction proteins ZO-1 and VE-cadherin. In short, our findings demonstrate that blocking EphB3 receptor signaling in the cerebral vasculature increases cvEC survival and reduces BBB permeability representing a potentially important therapeutic strategy for vessel repair and/or stability following TBI.

Keywords

Traumatic Brain Injury; Controlled cortical impact; endothelial cells; EphB3; ephrinB3; vasculature; blood brain barrier

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