Silencing Endothelial EphA4 Alters Transcriptional Regulation of Angiogenic Factors to Promote Vessel Recovery Following TBI

Traumatic brain injury (TBI) can cause a number of deleterious effects to the neurovascular system, including reduced cerebral blood flow (CBF), vascular regression, and ischemia, resulting in cognitive decline. Research into therapeutic targets to restore neurovascular function following injury has identified endothelial EphA4 receptor tyrosine kinase as a major regulator of vascular regrowth. The research outlined herein utilizes an endothelial-specific EphA4 knockout mouse model (KO-EphA4flf/Tie2-Cre) to determine the extent to which this receptor may influence vascular regrowth following TBI. Analysis of the colocalization and proximity of endothelial and mural cell markers (i.e. PECAM-1 and PDGFRβ, respectively) in immunohistochemically-stained brain sections demonstrates that EphA4 silencing does not seem to affect the physical association between, nor total amounts of, endothelial cells and pericytes, between genotypes by 4 days post-injury (dpi). Nevertheless, these measures demonstrate that these cell types may preferentially proliferate and/or expand into peri-lesion tissue in both KO-EphA4flf/Tie2-Cre) and WT-EphA4fl/fl mice. These data further suggest that both genotypes experience homogeneity of PECAM-1 and PDGFRβ expression between regions of the injury cavity. Gene expression analysis using mRNA samples from both genotypes reveals that KO-EphA4flf/Tie2-Cre CCI-injured mice experience increased expression of Vegfa, Flt1, and Fn (Fibronectin) compared to sham-injured condition knockouts. These results demonstrate changes in expression of angiogenic factors in the absence of early differences in patterns of vessel formation, which may underlie improved vascular regrowth, as well as outline a potential mechanism wherein the interplay between these factors and EphA4 silencing may lead to improved cognitive outcomes following TBI.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Translational Biology, Medicine, and Health

Department dc:contributor.department

Translational Biology, Medicine, and Health

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2020

Author dc:creator

• McGuire, David Robert

Chair dc:contributor.committeechair

• Chappell, John C.

Committee members dc:contributor.committeemember

• Robel, Stefanie
• Theus, Michelle H.
• Fox, Michael A.

• Ephrin receptor tyrosine kinase
• Vascular repair
• Pericytes
• Endothelial cells

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:26631

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/99318