UC San Diego

Throughout the body, the vasculature functions as a delivery system, supplying oxygen and nutrients crucial for cell activity and survival. Central nervous system (CNS) vasculature plays a second critical role as a barrier system, limiting brain entry of bloodborne ions, molecules, and cells. Indeed, CNS blood vessels are endowed with a series of unique properties that allow them to tightly regulate the extracellular environment of the brain, and together these properties are termed the “blood-brain barrier” (BBB). The barrier properties of CNS vasculature are critical for proper brain function; BBB dysfunction during disease or injury can lead to a cascade of consequences resulting in neuronal death. Several questions remain regarding how BBB properties are maintained in health and the mechanisms underlying their dysfunction in neuropathologies.

The brain uses an extraordinary amount of the body’s energy, and without constant blood supply from the vasculature, its functions quickly deteriorate. Indeed, neuronal activity leads to a temporary increase in local blood flow to provide neurons with sufficient energy and oxygen, and this phenomenon is known as neurovascular coupling (NVC). NVC has been shown to involve various cell types and signaling molecules, but it is still unclear to what extent endothelial cells, the cells that form the innermost walls of the vasculature, participate in NVC.

This dissertation explores brain vasculature in health and disease. Chapter I focuses on BBB dysfunction in disease, identifying PDLIM1 as a marker for BBB dysfunction and characterizing its role in CNS endothelial cells. Chapter II focuses on the neurovascular unit, specifically whether microglia play a role in maintaining barrier properties in healthy vasculature. Chapter III demonstrates the dynamic nature of neurovascular cholesterol metabolism and how this metabolic pathway influences NVC.