Date of Award

Spring 5-16-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

First Advisor

Valerie Odero-Marah, PhD

Second Advisor

Leonard M. Anderson, PhD

Third Advisor

Cimona V. Hinton, PhD

Abstract

Iroquois homeobox gene 3 (Irx3) is a transcription factor belonging to the Iroquois family of homeobox genes that is expressed in the embryonic organs of multiple organisms. Although much is known about Irx3 during embryogenesis, the cross talk of expression and function of Irx3 in peripheral vascular disease (PVD) remains to be investigated. Herein, we demonstrate that Endothelial PAS Domain 1 (EPAS1), which is involved in vasculogenesis and diseases associated with hypoxia, is an upstream regulator of Irx3, and this interaction contributes to the cellular movement of human microvascular endothelial cells (HMVECs). Genetic EPAS1 loss-of-function (LOF) studies in HMVECs resulted in a reduction of Irx3 mRNA, and Irx3-mediated endothelial cell migration in wound healing. In contrast, the effects of EPAS1 Gain-of-function (GOF) in HMVECs showed increased Irx3-mediated endothelial cell migration in wound healing. Taken together, these results reveal that Irx3 is an important regulator of cellular movement as a downstream target of EPAS1 signaling in HMVECs, which regulates migration.

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