Vascular Injury In Col3A1+/- Mice Model of Vascular Ehler-Danlos Syndrome

<p>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 <em>COL3A1 </em>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 C<em>OL3A1</em><em> </em>haploinsufficiency in the development of vEDS and develop new potential therapies for vEDS patients.</p> <p>Carotid ligation was applied to the <em>Col3a1^+/- </em>mouse as an injury model, and the results confirm that <em>Col3a1^+/- </em>mice have aberrant arterial injury repair. Arteries from the injured <em>Col3a1^+/- </em>mice showed increased cell proliferation, inflammation, and neovessel formation. <em>In vitro</em>, fibroblasts explanted from <em>Col3a1^+/- </em>mice have persistent myofibroblast status after treatment with TGF-β1, which validates the <em>in vivo </em>findings.</p> <p>Finally, two treatments were tested on <em>Col3</em><em>a</em><em>1</em><em>^+/-</em>mice after carotid ligation: bone marrow transplantation and celiprolol. Transplantation of <em>Col3a1^+/+</em> bone marrow to <em>Col3a1^+/- </em>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 <em>Col3a1^+/- </em>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2018

Author dc:creator

• ZHOU, Ping, MS

Contributors dc:contributor

• Dianna Milewicz
• Yang Xia
• Yong-jian Geng

• vEDS
• Col3a1
• bone marrow transplantation
• myofibroblasts differentiation
• TGF-β1
• wound healing
• Genetics
• Molecular Genetics
• Other Genetics and Genomics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/844

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1890