Therapeutic Targeting of Arteriogenesis Following Ischemic Stroke

Strokes are a leading cause of death and disability in the United States, predominantly caused by ischemic events. Ischemic strokes occur when a clot or other obstruction lodges in a blood vessel of the brain, restricting the movement of blood. Subsequent rapid cell death occurs and often leads to long term neurological deficits. Pial collaterals are a well-established determinant of patient outcome due to their unique ability to remodel into conductance arteries that can reroute blood back to the ischemic tissue. During development, pial collaterals arise within the pia mater and establish connections between distant arterioles of cerebral arteries. Under healthy conditions, these vessels are exposed to bidirectional blood flow, keeping them small and dormant. Following vascular obstruction, pial collaterals are exposed to unidirectional blood flow, triggering them to expand through an adaptive process termed, arteriogenesis, allowing for retrograde perfusion into the obstructed artery and its affected tissue. However, hyperacute arteriogenesis following ischemic stroke has been poorly investigated. The following dissertation aims to address this research gap and leverage the findings to develop therapeutics that enhance arteriogenesis. Previous research has revealed EphA4 restricts arteriogenesis through the Tie2 signaling axis, therefore this work sought to evaluate the endothelial cell (EC) specific role of the EphA4/Tie2 axis in acute arteriogenesis. EC-specific EphA4 KO mice displayed increased pial collateral size from 4.5 to 24-hours post-injury, which was associated with reduced tissue damage, improved cerebral blood flow, and enhanced motor function. Additionally, pharmaceutical stimulation of the Tie2 axis using Vasculotide, an angiopoietin-1 memetic peptide, replicates these findings. Administration of 3ug/kg Vasculotide to wildtype mice immediately after permanent middle cerebral artery occlusion leads to significantly larger pial collateral diameters, correlating with reduced tissue damage and improved functional recovery. Unlike Vasculotide, device stimulation using low intensity focused ultrasound failed to increase collateral diameter, despite resulting in profound neuroprotection. Taken together, this dissertation work demonstrates that the EphA4/Tie2 signaling pathway can be pharmacologically targeted to improve arteriogenesis following ischemic stroke.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biomedical and Veterinary Sciences

Department dc:contributor.department

Department of Biomedical Sciences and Pathobiology

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2023

Author dc:creator

• Kaloss, Alexandra M.

Chair dc:contributor.committeechair

• Theus, Michelle H.

Committee members dc:contributor.committeemember

• Morton, Paul
• Chappell, John
• Huckle, William R.

• Ischemic stroke
• collaterals
• EphA4
• Tie2
• Vasculotide

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10919/116094

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/116094