Date of Award

2016

Embargo Period

8-1-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Jeffrey Jones

Second Advisor

Donald R. Menick

Third Advisor

Amy Bradshaw

Fourth Advisor

Robin C. Muise-Helmericks

Abstract

Background: The thoracic aorta undergoes structural and mechanical changes with age, including dilation and increased collagen leading to decreased compliance. However, how age- dependent changes in resident cells mediate this aging process is not well understood. Previous studies have demonstrated a reduction in both ex vivo aortic contraction and in vitro collagen gel contraction by aortic smooth muscle cells (SMCs) from old mice relative to young, suggesting a deficit in aortic SMC contractility with age. Vascular SMCs are known to shift out of a contractile phenotype, with disease or mechanical injury, to remodel the extracellular matrix (ECM). Therefore, we hypothesized that aortic SMCs undergo a phenotype change with age that contributes to aortic structural and mechanical changes with aging. Methods/Results: Aortic SMCs were cultured from thoracic explants harvested from 6 month (“young”, n=6) and 21 month (“old”, n=6) C57 mice. Phenotype was defined by assessing proliferation, migration, adhesion, and gene expression. When measured over 7 days, old aortic SMCs displayed reduced proliferation relative to young aortic SMCs. In a modified Boyden chamber, migration by old aortic SMCs was reduced compared to young (13.4±1.0 vs. 28.8±4.8 migrated cells). Old aortic SMCs were less adherent to a poly-D-lysine surface after mechanical washing relative to young (12.6±1.3% vs. 23.3±1.9% adherence). A PCR array was used to measure the expression of ECM remodeling genes, including ECM proteins (collagens), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs. Increased expression of these genes produced a distinct genotypic profile in old aortic SMCs relative to young. Conclusions: With aging, aortic SMCs exhibit reduced proliferation, migration, and adhesion. Furthermore, old aortic SMCs have upregulated expression of ECM remodeling genes, including collagens. Together, these results suggest that altered aortic SMC phenotype plays an active role in aortic structural and mechanical changes with age.

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