Vascular Endothelium: Pharmacologic and Genetic Manipulations
Volume 294 in NATO ASI Series A, Life Sciences
John D. Catravas, Allan D. Callow, and Una S. Ryan, Editors. 308 pp.
New York, NY: Plenum Press; 1998. $110.00.
Since the publication of the now classic paper of Furchgott and Zawadzki in 1980, reporting the obligatory role of the endothelium in the modulation of the vascular responses to acetylcholine, the amount of attention to the endothelial regulation of vascular homeostasis has grown exponentially. Although the emphasis was initially placed on the regulation of vascular tone by endothelium-derived factors, it is now clear that endothelial cells participate in a wide variety of physiological processes that, in conjunction, control the behavior of the vascular system and therefore the blood flow supply to different organs. Consequently, abnormal function of the endothelium or endothelial dysfunction is at the core (either as a result or as a consequence) of several pathological conditions. Although a definitive book on the endothelium has yet to be published, there have been numerous attempts at gathering in one volume the enormous amount of information constantly poured into the medical literature and related to basic and clinical investigations of endothelial function and dysfunction. The present volume constitutes the proceedings of a NATO Advanced Research Workshop held in Crete, Greece, between June 22 and July 1, 1996, and is divided into six sections that cover a wide range of subjects.
The first and perhaps most interesting section of the book starts with a review of the relationship between endothelial and circulating cells with reference to the role of vascular injury in the expression of adhesion molecules. There is a chapter that deals with the molecular events that participate in the process of leukocyte adhesion to endothelial cells. In particular, it is known that the selectins (a family of proteins present on the membrane of leukocytes and endothelial cells) are pivotal in the initial steps of leukocyte attachment to the endothelium. Subsequently, other proteins such as integrin and members of the immunoglobulin superfamily on the endothelial cell surface make this attachment more stable. The selectin family includes three members: L-selectin found only in leukocytes, E-selectin found only in endothelial cells, and P-selectin found in both endothelial cells and platelets. These proteins seem to be specialized for the task of capturing leukocytes from the rapidly flowing bloodstream to the blood vessel wall. It is now clear that antibodies against the selectins can block leukocyte rolling, both neutrophils and lymphocytes. The importance of the selectins in the process of leukocyte adhesion to sites of inflammation has been recently underscored by the finding of impairment of neutrophil attachment to endothelial cells in vitro in a genetic disease called leukocyte adhesion deficiency (LAD). This chapter presents the reader with an in-depth discussion of the function of the selectins, their importance in the interaction between the leukocytes and the vessel wall and therefore in the role of leukocytes in inflammation, and finally the different molecular structures that are important for the role of the selectins. The section ends with a chapter focused on the relevance of the complement in the pathophysiology of different forms of lung injury, particularly in relation to the adult respiratory distress syndrome (ARDS).
In the second section, there is a review of two recent studies related to the investigation of the intracellular mechanisms that govern the activation of inducible nitric oxide synthase (NOS) in smooth muscle cells, particularly in relation to the possibility that lipopolysaccharide and cytokines may induce the activity of inducible NOS via a tyrosine kinase–mediated mechanism. Because the sustained production of large amounts of NO by inducible NOS may play a pivotal role in the pathophysiology of septic shock, these studies are important in providing insights into the cellular phenomena that characterize the activation of this enzyme. Another chapter reviews the mechanisms related to the process of adhesion of leukocytes to the endothelial cell layer and their migration across the endothelium to penetrate sites of inflammation. Importantly, within minutes of adhesion to the endothelium, leukocytes can transmigrate by a process that does not necessarily induce damage of the endothelial monolayer. In this process, there are adhesive proteins called cadherins, which are important for the control of endothelial permeability. Therefore, when these molecules are disorganized, endothelial permeability is significantly increased and the transmigration of leukocytes is enhanced. Interestingly, cadherins are complexed to other proteins inside the cytoplasm called catenins. The cadherin/catenin complex can be disorganized by neutrophil adhesion to endothelial cells, suggesting that leukocytes themselves could regulate the state of endothelial cell-to-cell junctions. The section ends with an excellent review of the postulated relation between the insertion/deletion polymorphism and coronary heart disease. This chapter is comprehensive, is written in a scholarly fashion, and presents the reader with a well-balanced discussion about genetic background for cardiovascular disease.
The next section relates to the fibrinolytic and antithrombotic actions of the endothelium. In particular, the plasmin/plasminogen system is reviewed in detail, as well as the role of tissue plasminogen activator in the prevention of intravascular fibrin deposition. An important section is devoted to discussion of how the primary cytokines such as interleukin-1 and tumor necrosis factor-α exert a stimulatory effect on the release of adhesion molecules by the vascular endothelium. There is a very brief review of the interactions between endothelium-derived NO and platelet function. The functional consequences of this process and the role of NO produced by the platelet themselves are also discussed.
The fourth section is related to inflammation and angiogenesis and describes in detail the role of different cytokines in the modulation of endothelial function. Importantly, cytokines are both produced by endothelial cells and are responsible for the activation of different processes within the endothelial cells that in turn will regulate vascular homeostasis and the response to different forms of vascular injury. There is a section on the molecular basis for the activation of proinflammatory molecules and a review of different pathological states in which these mechanisms play a significant role. Another chapter discusses the involvement of thrombin in the formation of new vessels in different conditions. Thrombin-induced angiogenesis has been shown to be receptor-independent and, more importantly, mediated by a receptor that is different from the one that participates in the clotting activity of thrombin. Of note, thrombin can activate different processes including endothelial cell migration, cell shape changes, disruption of endothelial cell barrier function, synthesis of platelet activating factor and thrombomodulin, and synthesis and release of tissue plasminogen activator and its inhibitor. Many of these effects of thrombin are related to its role in the angiogenesis process.
The fifth section contains a concise review of the brain circulation and its physiological regulation and a review of the nonatherosclerotic diseases of the cerebral vessels that affect blood delivery to the brain. There is a brief description of the cerebral autoregulation and the blood-brain barrier, with emphasis on the differences between brain circulation and circulation to other organs of the human system. The chapter does not concentrate on the role of the endothelium in cerebral circulation. Another chapter presents a relatively thorough review of the genetic factors associated with atherosclerosis, particularly, the methodology by which mouse models can be used to understand the genetic basis of atherosclerosis. There is also a detailed review of the role of the amyloid precursor protein and apolipoprotein in the fundamental structural abnormalities that lead to disarrangements that characterize Alzheimer’s disease. This review is scholarly and supported by an extensive bibliography. Potential mechanisms underlying the pathogenesis of Alzheimer’s disease are presented with a detailed discussion of the different studies supporting the corresponding hypotheses.
The last section includes a discussion of the anticancer therapeutic approaches involving gene delivery to arrest the angiogenesis associated with tumor growth. The potential for this form of treatment stems from the observation that the growth of solid tumors is dependent on the formation of new blood vessels. Thus, targeting the vasculature to impede angiogenesis appears to be an attractive alternative for the suppression of cancer growth. Finally, there is a review of the chemical reactions between NO and its biological targets, including the newly discovered role of NO as a modulator of gene expression. NO may modulate adenovirus-mediated gene transfer and has cytotoxic potential, particularly when produced at high and sustained concentrations. NO may also promote oxidant injury to proteins by rapidly reacting with superoxide anion to form peroxynitrite.
The book concludes with a presentation of 30 abstracts that were presented at the symposium; in conjunction, these abstracts cover extensive areas of physiological and pathophysiological roles of the vascular endothelium.
Like most symposium proceedings that are transformed into a book, this volume presents a collection of loosely organized chapters of uneven quality. The format and even the depth of the discussions included in the chapters are not homogeneous, and in some cases the title of the section does not reflect the content of its chapters. For example, Section 3 is titled “Thrombosis/Hypertension,” but there is no chapter on the role of the vascular endothelium in hypertension. The quality of the book is enhanced by the chapters relating to the role of the endothelium in inflammation and by those that represent a thorough review of the subjects, such as the chapter on the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the one related to the genetic factors in atherosclerosis.