Endothelial cell activation in inflammation: lessons from mutant mouse models Christopher G. Kevil * Department of Pathology, LSU Health Science Center, 1501 Kings Hwy, Shreveport, LA 71130, USA Abstract Dysregulation of the inflammatory response is a causative or contributing factor in many cardiovascular pathologies. Molecular mechanisms involved in these processes indicate that the vascular endothelium is an important facet in the regulation of inflammation. Gene targeted mutational studies in the mouse have shown that adhesion and signaling molecule expression within the endothelium participate in the pathogenic process of cardiovascular disease. These studies provide insight into genetic pathways that may be therapeutically relevant in both treatment and diagnostic regimens. However, we have also learned that the role of these pathways in endothelium during inflammatory diseases is complex, requiring further study to better understand specific mechanisms involved in endothelial cell dysfunction during cardiovascular disease. Alternative gene targeting techniques, such as the Cre  /loxP system, are beginning to allow tissue specific investigation of genetic pathways within the endothelium; however, extensive use of this technology is limited. This review discusses the role of the endothelium during inflammation and the insights that have been gained from the use of gene targeted mutant mice. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cardiovascular disease; Gene targeted mutation; Endothelium; Adhesion molecule; eNOS 1. Introduction The vascular endothelium is a regulatory organ ubiquitously distributed throughout the body. This organ mediates many diverse physiologic processes including the maintenance of an anti-thrombotic surface between the circulating blood and tissue, regulation of vascular tone through the release of vasodilator and vasoconstrictive agents, selective separation of vascular luminal contents from the tissues through barrier formation, and wound repair and tissue growth- mediated angiogenesis. The endothelium also plays a key regulatory role during inflammatory responses, controlling leukocyte adhesion and emigration through selective expression of cytokines, chemokines, and adhesion molecules. It is for these reasons that the endothelium is now widely considered the sentinel for cardiovascular health and disease. The vascular endothelium is centrally involved in many different cardiovascular disorders, including atherosclerosis, ischemia /reperfuion, diabetes, vasculi- tis, and stroke [1  /4]. These conditions appear to result from the dysregulation of one or more endothelial cell functions, which can ultimately lead to impaired vas- cular reactivity and endothelial cell injury. It is now clear that numerous biochemical and cellular interac- tions, focused on the endothelium, are required for vessel homeostasis and the pathogenesis of vascular disease. However, these interactions, as well as specific pathways that regulate them, remain largely undefined. During the last decade, many investigations have used gene-targeted mutant or knockout mice to more speci- fically determine gene functions in health and disease [5,6]. Fig. 1 illustrates the process by which gene targeted mutations are created in the mouse. The primary advantage of this approach is the ability to specifically analyze the function of single genes or to determine the importance of multiple genetic pathways in disease models. This approach has provided key insights into inflammatory pathophysiological condi- tions and led to interesting and unanticipated observa- tions [4 /6]. However, several difficulties have been encountered when using this approach, such as possible * Tel.:  /1-318-675-4694; fax:  /1-318-675-7662 E-mail address: CKevil@lsuhsc.edu (C.G. Kevil). Pathophysiology 9 (2003) 63  /74 www.elsevier.com/locate/pathophys 0928-4680/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0928-4680(02)00083-4