Date of Graduation

5-2018

Document Type

Dissertation (PhD)

Program Affiliation

Human and Molecular Genetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dianna Milewicz

Committee Member

Yang Xia

Committee Member

Yong-jian Geng

Committee Member

Min Sup Song

Committee Member

Ann Killary

Abstract

Vascular type of Ehlers-Danlos Syndrome (vEDS) is an inherited cardiovascular disease affecting the middle to large sized arteries, with an incidence rate of 1/5000. vEDS patients also show a significant phenotype of easily bruised skin, indicating aberrant wound healing and injury repair ability. Over 70% of the patients carry a glycine mutation located in their COL3A1 gene, which encodes the propeptide of type III collagen. Mutations in glycine residues lead to a disruption in the assembly and maturation of type III collagen. The goal and significance of the current study was to investigate the potential role of COL3A1 haploinsufficiency in the development of vEDS and develop new potential therapies for vEDS patients.

Carotid ligation was applied to the Col3a1+/- mouse as an injury model, and the results confirm that Col3a1+/- mice have aberrant arterial injury repair. Arteries from the injured Col3a1+/- mice showed increased cell proliferation, inflammation, and neovessel formation. In vitro, fibroblasts explanted from Col3a1+/- mice have persistent myofibroblast status after treatment with TGF-β1, which validates the in vivo findings.

Finally, two treatments were tested on Col3a1+/- mice after carotid ligation: bone marrow transplantation and celiprolol. Transplantation of Col3a1+/+ bone marrow to Col3a1+/- mice corrects the post-injury phenotypes, suggesting that bone marrow derived fibrocytes can be differentiated into myofibroblasts and produce sufficient type III collagen for successful wound healing. Celiprolol treatment on the Col3a1+/- mice also corrects the wound healing impairment by decreasing inflammation and cell proliferation. Therefore, this study validates a novel paradigm for vEDS that decreased supply of mature type III collagen fibrils affects fibroblasts in arterial wound healing and also provides evidence for bone marrow transplantation and celiprolol as potential new therapeutic approaches to the treatment of vEDS patients.

Keywords

vEDS, Col3a1, bone marrow transplantation, myofibroblasts differentiation, TGF-β1, wound healing

Available for download on Wednesday, May 01, 2019

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