The relationship between the cellular composition of the aortic adventitia and atherosclerosis

Abstract

Atherosclerosis develops in specific regions of the aorta due to an unknown cause. Transplantation experiments have led to the hypothesis that the initiating pathophysiological events of atherosclerosis result from intrinsic cues. The aortic media, the middle layer of the artery, is derived from multiple embryonic populations that have differential responses during atherosclerosis progression; it is unknown whether the adventitia, the outer layer of the artery, shares this heterogeneity. The adventitia is composed of multiple cell types and is involved in the progression of atherosclerosis. It was proposed that the embryonic origins and composition of the adventitia are associated with heightened atherosclerosis susceptibility. This study showed that the adventitia of the thoracic adult mouse aorta was composed of fibroblasts, SCA-1 positive cells, lymphatic vessels, macrophages, a vasa vasorum and neurons. By comparing ‘athero-susceptible’ and ‘athero-resistant’ regions, a positive association with athero-susceptibility and adventitial composition was inferred. Within athero-susceptible regions there were increased neuronal bodies and a decreased vasa vasorum. The embryonic origins of adventitial cells are unknown and were traced using Wnt-1 cre (neural crest cells) and Mef2c-AHF cre (secondary heart field cells) in adult transgenic mice which contained a mTmG reporter. This study revealed that a subset of adventitial cells had the same embryonic origin as the media, that the aortic root was derived from the secondary heart field, and the aortic arch and arch arteries were derived from neural crest cells. However, no association was observed between embryonic origin and atherosclerotic susceptibility. During atherosclerosis, adventitial progenitor cells are reported to migrate into the plaque. Exercise is an accepted treatment for the prevention of the clinical symptoms of atherosclerosis. Vascular progenitor cells, identified by mTERT-GFP expression, were observed in the adventitia and atherosclerotic plaques of atherosclerotic (ApoE-/-) mice. Exercise caused a decrease in the proportion of adventitial fibroblasts in ApoE-/-mTERT-GFP mice, but did not influence progenitor cell number. The research within this thesis provides novel data that the adventitia shows heterogeneity between regions of the aorta and indicates that this heterogeneity could aid in predisposing regions of the aorta to atherosclerosis.