Endothelial Cell Biology

1. Abstract

Human endothelial cells are multifunctional cells that line blood vessels and are capable of secreting a variety of biologically active mediators. They normally maintain vascular hemostasis and prevent thrombotic complications. When affected by infection, stress, hypertension, dyslipidemia, or high homocysteine levels, endothelial cells undergo changes resulting in “dysfunction,” characterized typically by decreased endothelial expression of nitric oxide, enhanced expression of cell adhesion molecules, and associated increased binding of circulating leukocytes to these cells. There is accompanying cytokine and chemokine elaboration, resulting in cellular recruitment and the orchestration of an acute inflammatory response that can culminate in chronic inflammation if reparative mechanisms are not operative. This review will address the basic biology of endothelial cells; the expression and regulation of endothelial-derived cytokines, chemokines, and growth factors; the transcriptional regulation of these genes in endothelial cells; and the role played by these fascinating cells in human disease.

Introduction

The human endothelium plays an essential role in normal physiology and in altered states such as atherosclerosis and sepsis. The normal physiologic functions of endothelial cells are listed (Table 1). These include regulation of several physiologic processes such as response to infection and sepsis (immune defense), alteration of coagulation and fibrinolytic systems, alteration of blood flow by synthesis of nitric oxide (NO), and wound healing. Such biologic processes are important in a variety of disorders (Table 2). Many of these disorders, such as malignancy, atherosclerosis, and sepsis, will be discussed later in this chapter.

The endothelium was once considered an inert lining of blood vessels. However, studies in the last 20 or more years have demonstrated the heterogeneity, functional promiscuity, and active role of these cells, both in physiology and in disease states. It is now apparent that endothelial cells express a variety of cell-surface molecules that mediate pivotal interactions, either between cell types (neutrophils, monocytes, and platelets) or between ligand–receptor pairs (pathogen–pathogen receptor, cytokine–cytokine receptor–integrin–cell adhesion molecule (CAM)). These interactions lead to endothelial activation in general. Endothelial activation is, in turn, accompanied by synthesis and secretion of inflammatory mediators such as cytokines, growth factors, and chemokines and altered expression of molecules important for the regulation of coagulation and plasminogen pathways. This paradigm could explain the activation of inflammatory and thrombotic pathways in sepsis, multiorgan failure, and coronary artery disease. The regulation of endothelial function may be mediated by key signaling molecules such as mitogen-activated protein kinases (MAPK) and transcription factors such as nuclear factor kappaB (NF-kappaB) (Fig. 1).