Date of Award

Winter 12-18-2015

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Lucy Liaw

Second Committee Member

Leif Oxburgh

Third Committee Member

Calvin Vary

Abstract

Following injury, smooth muscle cells in the wall of the blood vessel can switch from a quiescent, contractile phenotype to a migratory, proliferative phenotype which contributes to lesion formation and vascular occlusive disease. Important regulators of vascular smooth muscle cell phenotype include serum response factor and its cofactor myocardin, growth factors, Krüppel-like factors, microRNA-143/145 and Notch signaling. The Notch signaling pathway is highly conserved and plays a critical role in both vascular development and disease. In mammals, there are five Notch ligands (Jagged1, Jagged2, Delta-like 1, Delta-like 3, and Delta-like 4) and four Notch receptors (Notch1-4). Knockout mouse models of most of the Notch ligand and receptor components display early embryonic lethality due to abnormal vasculogenesis, indicating their essential role in cardiovascular development. Following injury, the vascular remodeling response incorporates unique contributions from several of the Notch ligand and receptor components. However, there are no studies to date exploring the loss of endothelial Delta-like 1 or the role of vascular smooth muscle Notch2 in the vascular remodeling process. The first aim of this work was to explore the hypothesis that conditional loss of vascular endothelial cell Delta-like 1 decreases neointimal lesion formation following injury due to loss of competitive inhibition of endothelial Jagged1. We performed carotid artery ligation in a transgenic mouse model with floxed Delta-like 1 and a vascular endothelial cadherin Cre driver, and found that loss of endothelial Delta-like 1 leads to a constrictive remodeling phenotype. The second aim tested the hypothesis that loss of vascular smooth muscle Notch2 increases neointimal lesion formation following injury by increasing vascular smooth muscle cell proliferation. Surprisingly, carotid artery ligation in a floxed Notch2 line with a smooth muscle-myosin heavy chain Cre driver decreased the resultant neointimal lesion size in comparison to control. In conclusion, we have identified two novel contributions to the remodeling response following injury. Characterization of the role of Notch signaling in vascular remodeling will assist in the development of more effective and targeted treatments for vascular obstructive pathologies, which are a major cause of morbidity and mortality in the United States and abroad.

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