Publication Date

5-2023

Date of Final Oral Examination (Defense)

3-14-2023

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Biology

Department

Biology

Supervisory Committee Chair

Richard S. Beard Jr., Ph.D.

Supervisory Committee Member

Cheryl L. Jorcyk, Ph.D.

Supervisory Committee Member

Juliette K. Tinker, Ph.D.

Abstract

Multiple Sclerosis (MS) is a severe demyelinating disease of the Central Nervous System (CNS) associated with an autoimmune response directed against myelin antigens. Angiogenesis, the formation of new blood vessels from preexisting ones, is a vital process for tissue regeneration and wound healing but is a pathological hallmark of both MS and an MS mouse model, experimental autoimmune encephalomyelitis (EAE). This type of aberrant angiogenesis is a fundamental event during an inflammatory injury, which is mutually dependent upon the intrusion of inflammatory molecules, disruption of the blood-brain barrier (BBB), and immature vessel formation. In the EAE recovery phase, this process is induced to repair tissue damage. Unfortunately, aberrant angiogenesis can lead to chronic lesion formation and slower recovery due to underdeveloped endothelial barrier integrity. A role for small leucine-rich proteoglycans (SLRP) in angiogenesis has been established in the periphery. However, their abundance in the CNS is typically low. Recently, the type I SLRPs, Decorin (DCN) and Biglycan (BGN), have been identified in MS and EAE brains, but their cellular source and functional role still need to be fully understood. Therefore, this study aimed to investigate the role of endothelial-derived DCN and BGN in EAE-induced aberrant angiogenesis. The hypothesis tested was that CNS endothelial knockout of SLRPs is associated with faster recovery in EAE-induced angiogenesis, BBB dysfunction, and clinical paralysis. We show that using endothelial-specific SLRP double knockout mice (BGN/DCNBBB/KO) reduces aberrant angiogenesis and significantly enhances the recovery of EAE. In addition, using in vitro assays, primary brain microvascular endothelial cells (BMVEC) lacking BGN/DCN were shown to have inhibited angiogenesis. Collectively, our data indicate that BGN/DCNBBB/KO) mice had faster recovery of EAE associated with reduced angiogenic progression. Future studies, potentially using genetic interventions, are needed to explore SLRP inhibition as a therapeutic approach to inhibiting aberrant angiogenesis in MS recovery.

DOI

https://doi.org/10.18122/td.2057.boisestate

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