Date of Award

2017

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Jeffery A. Jones

Second Advisor

Victoria J. Findlay

Third Advisor

Amanda C. LaRue

Fourth Advisor

Paul J. McDermott

Fifth Advisor

Michael R. Zile

Abstract

A reduction in microRNA (miR)-133a is associated with dilation of the thoracic aorta (TA). Since wall tension increases with vessel diameter, this study tested the hypothesis that elevated mechanical tension induces the loss of miR-133a in the TA. Elevated tension (1.5g, 3hrs) applied to murine TA ex vivo reduced miR-133a (0.31±0.17 vs 1.00±0.25 fold; p<0.05 vs normotension (0.7g)). Cyclic stretch (12%, 1Hz, 3hrs) reduced miR-133a in TA fibroblasts (0.21±0.02 vs 1.00±0.27 fold; p<0.05 vs static control), with no change in smooth muscle cells. Neither transcription of miR-133a nor mRNA/protein levels of three microRNA-specific exoribonucleases were altered with stretching of the fibroblasts. However, stretch induced exosome secretion of miR-133a. Two in vivo models of hypertension were utilized to determine the effect of elevated wall tension on miR-133a in the TA: Angiotensin-II infusion (1.44mg/kg/day, 28 days) and a spontaneous hypertensive mouse line (BPH2). In both models, blood pressures were elevated and miR-133a was decreased in the TA compared to normotensive mice (0.69±0.06 and 0.52±0.04 vs 1.00±0.13 fold respectively; p<0.05 for both). Plasma miR-133a was elevated in the BPH2 mice (3.39±0.77 vs 1.00±0.41 fold; p<0.05 vs normotensive). Plasma miR-133a was also elevated in hypertensive human subjects (1.55±0.26 vs 1.00±0.18 fold, p<0.05 vs normotensive). These findings demonstrate that the reduction in miR-133a levels that occurred with increased mechanical stretch of the TA was likely driven by exosome secretion from TA fibroblasts, and may provide a novel target for detrimental remodeling of the vasculature in the setting of hypertension.

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All rights reserved. Copyright is held by the author.

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