(Hypertension. 1998;32:786-787.)
© 1998 American Heart Association, Inc.
Book Review
Julio A. Panza, MD1
1 Section on Echocardiography,
Cardiology Branch,
National Heart, Lung, and Blood Institute,
National Institutes of Health,
Bethesda, Md
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.
ISBN 0-306-45819-5
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-
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.
