Characterization of The Vascular Pathology In The Acta2 R258C Mouse Model and Cerebrovascular Characterization of The Acta2 Null Mouse

<p>Mutations in<em> ACTA2, </em>the gene encoding for smooth muscle α-actin, predispose patients to a wide range of vascular diseases and is most commonly associated with thoracic aortic aneurysms (TAAD) and dissections (TAAD) and strokes. TAAD in patients is characterized by aortic media degeneration and loss in contractile force generation followed by aortic enlargement and subsequent rupture. Most stroke cases associated with <em>ACTA2</em> are described as moyamoya-like cerebrovascular incidents characterized by distal occlusion of the internal carotid artery, stenosis of arteries in the Circle of Willis, and straightening of cerebral arteries. Patient samples are scarcely available for analysis, and the few obtained are from end stages of the disease. For these reason, we decided to study the causative mechanisms of vascular disease using the <em>Acta2^R258C</em>transgenic and <em>Acta2^-/-</em> mouse models.</p> <p>The aortic phenotype was studied using the transgenic mouse model bred with Acta2^-/-mice to decrease the <em>ACTA2</em> wildtype to mutant ratio. <em>Acta2^{+/+ R258C TG}</em>mice have decreased aortic contractility and mild medial wall degeneration but no evidence of aortic enlargement was observed. However, <em>Acta2^{+/- R258C TG} </em>mice showed severe aortic wall degeneration, elastic fiber rupture and proteoglycan accumulation along with significant aortic dilation. After carotid artery ligation, <em>Acta2^{+/- R258C TG} </em>mice presented with an excessive proliferative response to injury, leading to increased inflammatory response, unresolved thrombi and severe occlusion of the lumen.</p> <p>Cerebral imaging and histology were studied in WT, Acta2^+/-, Acta^-/-mouse mode. Straightening of the cerebrovascular arteries was observed in <em>Acta2^+/-</em> and <em>Acta2^-/-</em> mice when compared with WT mice. Narrowing and/or obstruction of arteries were also present in the <em>Acta2</em> mutant mice, in particular in the internal carotid arteries. Histopathologic analysis showed thickening of the medial layer in both large and small arteries throughout the vasculature with decreased cell density in the large arteries.</p> <p>We were able to recapitulate significant characteristics of the aortic and cerebrovascular pathology seen in patients with <em>ACTA2</em> mutations in our <em>Acta2</em> mouse models, proving to be a valuable tool to study the underlying mechanisms of vascular disease. Furthermore, both aneurysm formation and SMC proliferative response were exacerbated by decreasing the amount of endogenous <em>Acta2</em> in our transgenic model. The severity of the cerebrovascular pathology did not vary between <em>Acta2</em>^+/- and Acta^-/-, suggesting a dose dependent effect in these mice. Meanwhile, the <em>Acta2</em> R258C mutation appears to have a dominant negative effect, as its effects are inversely correlated to the amount of endogenous actin in an organism.<strong></strong></p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2014

Author dc:creator

• Villamizar, Carlos A

Contributors dc:contributor

• Dianna Milewicz MD PhD
• Ananth Annapragada PhD
• Jaroslaw Aronowski PhD

• ACTA2
• Aneurysm
• Dissection
• Aorta
• Stroke
• Cerebrovascular
• Mouse Model
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/508

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1548