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Cellular and Molecular Basis for Postnatal Growth and Adult Regeneration of the Mouse Aorta

  • Author(s): McDonald, Austin Ian
  • Advisor(s): Iruela-Arispe, Luisa
  • et al.
Abstract

Endothelial cells form a monolayer of cells on the luminal surface of blood vessels. Over the last several decades, investigators have reported numerous successes elucidating the cellular and molecular mechanisms by which endothelial cells can direct the sprouting formation of small capillary blood vessels (angiogenesis) with concomitant expansion of the total surface and number of cells composing the endothelial lining, with important implications for human disease. However the mechanisms which apply in the case of lining expansion in large arteries, the primary location for human atherosclerotic disease, is unknown. Knowledge of how the lining grows and regenerates damage under physiological conditions provides important insight into the failure of the lining in the diseased state. Progress in study of this process has been limited due to technical difficulties and challenges. Isolated endothelial cells grown in a dish have poor fidelity to the same cells in their native context of a pulsating artery. They lack circulating blood and the complex interactions between endothelial cells, vascular smooth muscle cells, and circulating blood cells. Meanwhile, the arteries of mammals, the gold standard for extrapolating to humans, are difficult to study due to the need for surgical access and a much more limited suite of experimental tools.

This thesis addresses important unknowns in the biology of the mammalian endothelial lining of arteries using an in vivo mouse model. Specifically, it answers the following questions currently outstanding in the field of vascular biology: 1) When more endothelial cells come to exist in the endothelial lining, where do they originate? 2) Is there an endothelial stem or progenitor cell which persists past the embryonic stage to supply new endothelial cells to growing or damaged vessels? And 3) Does the expansion of the endothelial lining to cover new area within large vessels share the same molecular organization as angiogenesis?

In Chapter 2, I present work which uses clonal cell tracing experiments to show that during the postnatal enlargement of the aorta, the largest vessel in the body, the division of existing endothelial cells within the arterial lining itself is sufficient to explain the entirety of the increase in length and circumference of the lining. In Chapter 4, I use a surgical method to damage the lining of the adult aorta and observe its regeneration. Through lineage tracing, parabiosis, and clonal tracing experiments I show that in fact a progenitor subpopulation exists within the adult arterial lining, and these cells supply the majority of the new endothelial lining. In Chapter 3, I report the results of molecular profiling of endothelial cells participating in the regeneration of the endothelial lining of the mouse aorta by transcriptomic sequencing, and follow up with immunocytochemistry validating the selective expression of key regulatory proteins in the regenerating lining and not in the surrounding lining or in the angiogenic neonatal mouse retina.

In sum, my work shows that endothelial lining growth and regeneration are the result of highly localized endothelial cell proliferation within the lining of the aorta itself, and in the case of regeneration demonstrates the ability of cells within the lining to either acquire or intrinsically possess a transient amplifying phenotype. The results indicate that hypothesized circulating or bone-marrow derived endothelial stem or progenitor cells do not exist, at least in the postnatal and adult mouse. Finally, they show that the regenerative process is molecularly distinct from the well-studied case of angiogenic proliferation, opening a new mode of endothelial lining expansion to further investigation.

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