Abstract-Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium. (Circ Res. 2007;100:158-173.)

Severe sepsis, defined as sepsis with acute organ dysfunction, is associated with high morbidity and mortality rates. The development of novel therapies for sepsis is critically dependent on an understanding of the basic mechanisms of the disease. The pathophysiology of severe sepsis involves a highly complex, integrated response that includes the activation of a number of cell types, inflammatory mediators, and the hemostatic system. Central to this process is an alteration of endothelial cell function. The goals of this article are to (1) provide an overview of sepsis and its complications, IntroductionSepsis is the most common cause of death among hospitalized patients in noncoronary intensive care units. Thus, an important goal in critical care medicine is to develop novel therapeutic strategies that will impact favorably on patient outcome. Unfortunately, the pathophysiology of severe sepsis remains poorly defined. While it is generally accepted that sepsis-associated mortality is related to the host response and involves a multitude of cell types, inflammatory mediators, and coagulation factors, clinical studies have largely failed to identify an effective therapeutic target. Future advances in sepsis therapy will require a better understanding of how the individual components of the host response interact. The endothelium plays a critical role in mediating the sepsis phenotype. This article provides an overview of sepsis and its complications, discusses the role of the endothelium in orchestrating the host response in sepsis, and emphasizes the potential value of the endothelium as a target for sepsis therapy. Overview of the sepsis continuum DefinitionSepsis and its sequelae represent a continuum in clinical-pathologic severity. However, it is one with definable phases that characterize patients at risk for increased mortality. 1 The American College of Chest Physicians and the Society of Critical Care Medicine established a set of definitions to facilitate early detection and treatment of sepsis and to standardize patient requirements for research protocols. 2 Infection is defined as an inflammatory response to microorganisms or the invasion of normally sterile host tissue by those organisms. Sepsis represents the systemic inflammatory response to infection and is manifested by 2 or more of the systemic inflammatory response syndrome (SIRS) criteria (eg, changes in body temperature, tachycardia, tachypnea and/or hyocapnia, and changes in the number and/or immaturity of white blood cells). Severe sepsis is sepsis complicated by organ dysfunction. Septic shock (hypotension despite adequate fluid resuscitation) is a subcategory of severe sepsis. At the end of the spectrum is multiple organ dysfunction syndrome (MODS), defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. EpidemiologyIn 1990, the Centers for Disease Control and Prevention reported an estimate of 450 000 cases of septicemia per year in the United States, ...