Date of Award

11-3-2009

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

George Tellides, M.D., Ph.D.

Abstract

Vascular diseases such as atherosclerosis or aneurysmal disease preferentially affect different parts of the arterial system. Despite this heterogeneous pattern of disease within the arterial system, the contribution of different smooth muscle cell phenotypes to this pattern has not been well studied. We investigated aortic disease susceptibility and epigenetic differences within different regions of the murine aorta. Quantitative analyses showed more numerous atherosclerotic plaques and larger aneurysms in the ascending aorta compared to the descending thoracic aorta in apoE-/- and fbn1C1039G/+ mice, respectively. Interferon-γ and transforming growth factor-β responses, characteristic of these disease processes, were greater in the ascending vs. descending thoracic aorta. There was differential gene expression within the aorta and a "Hox code" was found for the murine arterial vasculature along the anteriorâposterior axis. Transplantation ofascending and descending thoracic aortic segments to the abdominal aorta of syngeneic recipients confirmed that the propensity for atherosclerotic disease and the expression of selective molecular markers were innate properties of the vessel wall and not dependent on regional hemodynamic factors or paracrine signals from surrounding tissues. The epigenetic changes were also stable in cultured cells despite identical in vitro conditions. Our work supports the concept of intrinsic differences between vascular smooth muscle cells from various arteries that may play a role in disease pathogenesis.

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