Peripheral vascular disease affects tens of millions of people in the United States alone and is a significant cause of morbidity. Occlusive lesions in vessels limit blood flow to distal tissues creating a hypoxic environment. The vasculature responds by increasing angiogenic growth of new vessels and arteriogenic remodeling and maturation of existing vessels. In hypoxic conditions, hypoxia inducible factor 1 (HIF-1) is a key transcription factor in controlling endothelial response and subsequent vascular changes. Despite the attention focused on their endothelial neighbors and their importance in the integrity of the vessel wall, the role of vascular smooth muscle cells (VSMCs) in promoting and contributing to reperfusion is not well understood. This project examines the role of HIF1 and hypoxia in the regulation of VSMCs, and is driven by the hypothesis that HIF-1 in peripheral VSMCs plays a critical role in arteriogenesis and angiogenesis. While peripheral vessels are a common location of disease and are often used in revascularization therapy, published literature focuses on cells isolated from central and neonatal umbilical vessels. Characterizing the phenotypic responses of isolated adult peripheral arterial and venous VSMCs to hypoxia at the cellular and molecular level will provide a framework for understanding the responses seen in research models and in patients. For further clarity, examining the mechanism of regulation both upstream and downstream of HIF-1 will determine the regulatory role of HIF-1 as well as factors and pathways at play in VSMCs' responses to hypoxia. Finally, role of HIF-1 in facilitating vascular response promoting reperfusion will be investigated in a murine model of limb ischemia. These studies will expand the current view of VSMCs within their native environment of the vessel wall and will contribute to a more complete understanding of vascular responses to vessel occlusion. Understanding the mechanisms and cells responsible for vascular growth and remodeling changes seen in ischemia and its hypoxic sequelae will aid in therapeutically enhancing reperfusion efforts and preventing pathologic consequences.
Peripheral vascular disease is a major cause of morbidity decreasing circulation in the limbs. This project examines the contributions of HIF in vascular smooth muscle to restore blood flow to depleted tissues. Better understanding of cellular contributions will help to inform the development of medical therapies and surgical interventions to treat this prevalent disease.
