For many centuries man has been both captivated and perplexed by the brain and its workings. Whole body physiology is coordinated predominantly via complex and intricate brain processes that are only vaguely understood. As such the search continues to unravel what many individuals, scientists and lay men alike, consider the most important organ for our physiological function and indeed “humanness”.
Within the brain there are many different cells that function continuously to coordinate body processes such as endothelial cells, astrocytes, pericytes, neurons, microglia and others. Although neurons are frequently considered to be the most important it must be remembered that crosstalk between all brain cell types is what enables the maintenance of a highly privileged environment that is permissive to support proper neuron function. Indeed what would be the point of leaving the kingdoms stash of gold unprotected? Surely such an oversight would result in a loss of the treasure and collapse of the empire. Since our ultimate goal is to protect the treasure (neurons) from the perpetrators of damage we must consider responses of not only the cells that are the master coordinators of body physiology (i.e neurons) but also the cells that protect them in our attempts to understand brain function and improve recovery after injury.
At the heart of brain homeostasis is the blood-brain barrier (BBB) - the gateway to the brain parenchyma. The BBB is a microvascular network that exists throughout the brain and is composed of a vascular endothelium that has close and complex interactions predominantly with astrocytes and pericytes. In this regard it is paramount to know that disturbance of BBB function, especially via oxygen and/or ischemic conditions, allows entrance of foreign substances to the brain tissue and results in neuronal hyper-activation and dysfunction. The primary aim of my research presented herein is to convey to the reader the important contribution of different brain cells and their signaling mechanisms to physiological BBB development and stability, as well as its disruption during disease progression. The first chapter provides the reader with an introduction to the BBB and some of the major advances made during the last few decades. The following chapters present published work performed to understand the contribution of individual cell types to barrier stability and disturbance using classic and novel in vitro and in vivo systems. Evidence shows the differential impact of perivascular cells on endothelial characteristics via activation of different signaling mechanisms but also physical localization during both physiological and pathological conditions. Understanding the influence of HIF-1, the master regulator of hypoxic responses, on barrier function is also untaken and negative effects of sustained activation of the HIF-1 pathway on vascular stability in vivo using transgenic mice is also presented. The final chapters discuss the overall impact of these findings and highlights an agenda for further work and future obstacles that must be considered to be able to reach the goal of protecting and/or modulate barrier function effectively.