(Circulation. 2000;102:IV-112.)
© 2000 American Heart Association, Inc.
Special Anniversary Issue |
Vascular Biology: The Past 50 Years
From the Department of Medicine, Emory University School of Medicine, Atlanta, Ga (R.W.A.), and Harvard Medical School and Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (V.J.D.).
Correspondence to R. Wayne Alexander, MD, PhD, Department of Medicine, Emory University School of Medicine, Emory University Hospital, Suite H-153, 1364 Clifton Road, NE, Atlanta, GA 30322.
Key Words: vasculature • endothelium • atherosclerosis
It is an interesting endeavor to review progress in a field that did not exist 50 years ago in the present context of the term "vascular biology." Certainly, in 1950, there was basic understanding of the role of arteries and veins in cardiovascular physiology and of capillaries in gas and nutrient transport. Furthermore, there was considerable clinical knowledge about the role of atherosclerosis in ischemia and infarction of the heart and other organs and that of hypertension in inducing microvascular damage and organ failure, particularly in the kidney. "Vascular biology," which connotes the study of the biology of the constituent cells of the normal and diseased vascular wall, first gained some currency in the 1970s in defining this new field of study, which has enjoyed explosive growth in the past 25 years. Thus, the state of knowledge in 1950 must be placed in the modern context inferentially.
Vascular Biology, 1950
The vascular smooth muscle cell was appreciated for its
role in controlling vascular tone in the resistance arteries.
Nitroglycerin had been known for decades to relieve angina pectoris,
and Osler had speculated about the role of vasospasm in precipitating
ischemia and infarction. It was presumed, although not generally
specifically stated, that hypercontractility of a particular coronary
artery segment was being invoked, inferentially indicting the vascular
smooth muscle cells. The endothelium was known to be a nonthrombogenic
surface, although little was understood of the underlying molecular
mechanisms. Conversely, acute cardiovascular ischemic events, such as
stroke and myocardial infarction, were known to be associated
frequently with localized arterial thrombus formation. As alluded to
above, investigators knew that hypertension damaged blood vessels but
did not know the specific mechanisms involved. Finally, investigators
knew that atherosclerosis itself involved inflammatory cell and lipid
accumulation in the arterial wall, although their mechanisms of entry
were not known. These facts are summarized in the
Table
.
|
Vascular Biology, 2000
Endothelium and Endothelial Dysfunction
A central role in the pathogenesis of atherosclerosis
for the endothelial cells that line the arterial wall was posited in
the 1970s, when it was discovered that their removal by mechanical
means dramatically enhanced the ability of a high-lipid diet to induce
the disease in animal
models.1 These
observations led to the original response-to-injury hypothesis of the
pathogenesis of
atherosclerosis.1
Subsequent observations in humans and animal models in the late 1970s,
however, usually showed that the endothelium overlying atherosclerotic
lesions was morphologically intact. To rationalize these apparently
inconsistent observations, Gimbrone proposed the concept of endothelial
dysfunction that acknowledged the central role of the normal
endothelium in protecting against the development of atherosclerosis
while positing that its cellular functions were abnormal in this
setting. "Activation" of endothelial cell inflammatory responses by
cytokine stimulation in in vitro studies became something of a
surrogate for gaining molecular insights into potential mechanisms for
endothelial dysfunction in vivo.
Endothelium-Derived Relaxing Factor/Nitric
Oxide
Arguably, the most momentous changes that have occurred
in the field of vascular biology in the past 50 years have been the
discovery and elucidation of the endocrine/paracrine roles of the
endothelium. Initial insights into the endothelium as a modulator of
the hormonal milieu resulted from the observation that generation of
angiotensin II from angiotensin I was dependent on
angiotensin-converting enzyme (ACE) located at the endothelial surface.
Hormonally regulated release by endothelial cells of vasoactive
prostaglandins was described in the
mid-1970s,2 and
prostacyclin (PGI2), which was both a
vasodilator and a platelet anti-aggregatory agent, was subsequently
described as an endothelial
product.3 The most
seminal event in this area, however, occurred in 1980. Robert
Furchgott, who was later to win the Nobel Prize, described the
phenomenon of endothelium-dependent
vasorelaxation.4 In
simple but elegant experiments, he and his colleagues showed, in in
vitro experiments in organ baths, that preconstricted arterial rings
would relax in response to muscarinic cholinergic agonists only if
endothelial cells were present. Removing the endothelium by any means
abolished the vasorelaxation, which was mediated by an undefined
endothelium-derived substance that was named endothelium-derived
relaxing factor (EDRF). EDRF subsequently was shown to be, in large
part, nitric oxide
(NO),5 6
which diffuses to the underlying vascular smooth muscle and stimulates
the second-messenger cGMP to cause relaxation. Many, if not most,
vasodilator stimuli, such as flow and multiple
G-protein–coupled receptors, including those for serotonin and muscarinic
cholinergic agonists, act through this indirect, endothelium-dependent
mechanism.7 8
Vasospasm and Endothelial Dysfunction
Attilio Maseri and his colleagues demonstrated coronary
vasospasm angiographically in patients with unstable coronary syndromes
in 19789 and
initiated a period of intense interest in vasomotor abnormalities
across the spectrum of coronary artery disease. Thus, in the early
1980s, there was a confluence of ideas—endothelial dysfunction as a
cause of atherosclerosis, the endothelium as a major determinant of
vasomotor tone, and coronary artery spasm as an important element in
ischemic syndromes—that led to the development of major new insights
into vascular biology at both the basic and clinical levels. The issue
was whether the endothelial abnormality (dysfunction) that was
associated with the development of coronary atherosclerosis also
involved the endothelium-dependent vasodilator mechanism described by
Furchgott. Furthermore, such an abnormality might contribute to
coronary vasospasm, which could be evaluated clinically. The results of
a study evaluating these possibilities were published in
1986.10 The
endothelium-dependent vasodilator acetylcholine, a muscarinic
cholinergic agonist, was infused selectively into the arteries of
patients with stable angina pectoris who were undergoing PTCA.
Acetylcholine predictably dilated angiographically normal segments but
produced a paradoxical vasoconstriction in segments with either severe
stenoses or minimal angiographic disease. Stimulation of the
sympathetic nervous system with cold pressor testing elicited similar
results.11 These
observations provided some of the initial evidence for abnormalities in
endothelial function in coronary artery disease and contributed to the
development of vascular biology as a clinically important
science.
Abnormalities of endothelial function, as reflected in disordered vasomotor control, have been demonstrated both in large arteries and in the microvasculature in multiple cardiovascular diseases in addition to atherosclerosis and including systemic and pulmonary hypertension and congestive heart failure. Many of the risk factors associated with cardiovascular disease, including diabetes mellitus, smoking, dyslipidemias, and low-estrogen states, are also associated with endothelial dysfunction. These associations suggested that there might be common mechanisms through which endothelial function is being perturbed, as will be discussed below. In addition, improvement in disordered vasomotor tone control after therapeutic interventions was quickly perceived to be a potential measure of clinical efficacy. This issue will also be discussed subsequently.
Inflammation, Atherosclerosis, and
Endothelial Dysfunction
Abnormalities in endothelial vasodilator function,
although they are likely to be clinically important, are really a
surrogate for the more important question of how this dysfunction
relates to the pathogenesis of atherosclerosis. As noted above, the
fundamental inflammatory nature of atherosclerosis has been known in
principle, but not really appreciated, for decades. A number of
publications from the mid-1980s onward have emphasized the importance
of inflammation in the disease process as reviewed by Munro and
Cotran.12 Postmortem
analysis of infarct-related lesions in coronary arteries showed a
localized inflammatory response manifested by intense accumulations of
mononuclear cells.13
The mechanisms by which these inflammatory cells are attracted into the
arterial wall became a major focus of research. Considerable progress
had been made from in vitro studies in defining leukocyte adhesion
molecules that appeared on the endothelial surface after cytokine
stimulation, and reagents (antibodies) were developed for binding and
identifying these inducible
proteins.14 This
technology was then applied to the study of arteries of rabbits after
several days of cholesterol
feeding.14 Monocyte
adhesion was observed at branch points in areas of low or disturbed
flow that are known to be sites of predilection for the development of
atherosclerotic lesions. In some cases, the mononuclear cell had
entered into the cell wall and was located just beneath the overlying
endothelial cell. In either instance, there was evidence of the
expression on the endothelial cell surface of a new protein that was
found to be the rabbit equivalent of human vascular cell adhesion
molecule-1 (VCAM-1), which, through interaction with its counterligand
VLA-4, causes adhesion of monocytes and T cells to endothelium. Thus,
VCAM-1 became the prototype for what is undoubtedly a set of molecules
that is stimulated by a hyperlipidemic milieu and that is involved in
recruiting mononuclear cells into atherosclerotic lesions. These data
raised the question, in the specific context of VCAM-1, of the identity
of the intracellular signaling pathways in endothelial cells that
stimulate the expression of adhesion and chemoattractant
molecules.
Oxidation in Vascular Regulation
One of the major developments in vascular biology over
the past 15 to 18 years has been the understanding of the importance of
oxidation mechanisms in mediating physiological and especially
pathophysiological responses in blood vessels. The seminal observations
came initially from the Steinberg group in San Diego and subsequently
from the Fogelman group in Los Angeles. The original observation was
that cultured mononuclear cells would not take up freshly isolated LDL
to form lipid-laden foam cells (the characteristic cell of the
atherosclerotic lesion) but that exposure of the LDL to cultured
endothelial cells modified the lipoprotein so that it was taken up by
the monocytes/macrophages to form foam
cells.15 The
modification of the LDL that permitted recognition and uptake was an
oxidative one, and oxidized LDL was found to have protean biological,
proinflammatory activities
itself.16 Thus, an
extracellular oxidation mechanism is thought to be centrally important
in the cell biology of atherosclerosis. The UCLA group has made a
compelling case for the role of minimally oxidized LDL as an initial
proinflammatory stimulus that differs in a number of fundamental
aspects from more extensively oxidized
LDL.17 The primary
point to be made here is that oxidative stress is a fundamental feature
of
atherosclerosis.18 19
Extrapolating from the points about endothelial dysfunction made earlier, it is apparent that the vasomotor control abnormalities seen in atherosclerosis are occurring in the presence of oxidative stress, ie, the production of excessive amounts of reactive oxygen species (ROSs). These facts were important because, in a larger context, they suggested a molecular mechanism for endothelial dysfunction. It had been known earlier that NO, which itself is a radical, is degraded and inactivated by oxygen free radicals, the ultimate source of many ROSs. A series of papers by Harrison and colleagues in the early and mid 1990s provided compelling evidence that both hypertension and atherosclerosis are associated with enhanced production of oxygen free radicals as directly measured and at a time when NO production is continuing but endothelium-dependent relaxation is impaired. Inferentially, NO is being degraded and inactivated.20
The demonstration of enhanced ROS production in settings
known to be associated with inflammatory responses in arteries
(atherosclerosis and hypertension) raised the possibility that
oxygen-derived radicals might be involved in the intracellular
signaling events controlling VCAM-1 gene expression. In fact, the gene
for endothelial VCAM-1 is regulated by a reduction/oxidation
(redox)-dependent activation of the transcription factor
NF-
B.21 A number
of intracellularly active antioxidants inhibit VCAM-1 expression in
vitro in cultured endothelial cells and in hypercholesterolemic animal
models. In these models, fatty streak and foam cell formation can be
inhibited even in the presence of very high plasma cholesterol levels,
raising the possibility that certain antioxidants may inhibit
atherosclerosis by mechanisms other than the inhibition of the
oxidation of LDL.
NO itself is a powerful antioxidant and is generated from the amino acid arginine by one of several isoforms of the enzyme NO synthase (NOS). Normal synthesis of NO by the arterial and microvascular endothelium is probably essential for normal vascular health. NOS is a highly regulated enzyme and is probably diminished in advanced arterial disease. Endothelial NOS is upregulated by HMG-CoA inhibitors, and some of their clinical efficacy may be due to their enhancing the antioxidant potential of the arterial wall through this mechanism.
In pathological circumstances, NO can also become a prooxidant. In the presence of high concentrations of oxygen free radical, high concentrations of NO (which can be produced by a different NOS isoform in macrophages/foam cells as well as by the NOS in endothelial cells), the 2 molecules can combine to form the highly reactive radical peroxynitrate. Peroxynitrate can modify proteins and change their function and thus contribute to the general vascular dysfunction in atherosclerosis and hypertension.
Redox-mediated mechanisms serve very important functions in multiple aspects of vascular biology and pathophysiology, a discovery made in approximately the last 15 years. The therapeutic implications of these new insights are currently being investigated.
Angiotensin II
The peptide angiotensin II was identified by the 1950s
as a major pressor activator derived ultimately from the
kidney.22 23
The physiology of the renin-angiotensin system was well characterized,
and its role in renovascular hypertension was defined by the 1960s and
1970s. The requirement for conversion of the precursor angiotensin I to
angiotensin II by a peptidase activity to generate a pressor effect was
understood. The physiological importance of this activity and that of
the enzyme that was named ACE became known with the discovery in the
1960s of inhibitory peptides derived from a South American toad that
blocked the pressor effects of angiotensin I. The development of oral
ACE inhibitors and the demonstration of their wide clinical efficacy
were intellectual triumphs of the past half-century.
The physiology and cell and molecular biology of the renin-angiotensin system in general and of angiotensin II in particular were extensively characterized between 1975 and 2000.24 For approximately the first 15 years of that time, angiotensin II was generally viewed primarily as a uniquely potent and important vasopressor. In retrospect, the first suggestion that angiotensin II might have a broader role in vascular biology was the observation by Laragh and his colleagues in 197225 that patients with high-renin (and thus high–angiotensin II) hypertension had a higher cardiovascular mortality rate than did those with low-renin hypertension. He and his group convincingly confirmed their earlier observations in 1992, the same year that 2 major trials studying the effects of ACE inhibitors on the development of congestive heart failure and ventricular remodeling after acute myocardial infarction, SAVE and SOLVD, also reported a decrease in recurrent cardiac ischemic events.26 These studies raised the possibility, although it was not fully articulated at the time, that angiotensin II might have direct atherogenic, ie, vascular proinflammatory and proliferative, actions.24 27 In the early 1990s, however, there was no or little experimental context in which the findings could be understood at a mechanistic level. This situation changed rapidly over the rest of the decade.
Angiotensin II was found to induce oxidative stress on vascular cells in culture and in arteries in animal models.18 20 Infusion of the peptide into rats produced hypertension that was associated with endothelial dysfunction in much the same fashion as did hypercholesterolemia, as discussed earlier. The model of oxidative stress–induced vascular proinflammatory responses described previously would predict that hypertension produced experimentally by angiotensin II would be associated with arterial infiltration by mononuclear leukocytes. In fact, this was precisely what was observed. Thus, angiotensin II is a potent proinflammatory molecule for blood vessels. It is also a potent growth factor for vascular smooth muscle and a major mediator of vascular growth and development.
Thus, the early clinical trials that inferred a major role for angiotensin II in the pathogenesis of atherosclerosis and acute cardiovascular events can now be understood, to an important extent, mechanistically in terms of the underlying vascular biology.
Vascular Smooth Muscle Cells and Vascular
Remodeling
In 1950, the vascular smooth muscle was thought
to have the sole function of controlling vascular tone through
contraction or relaxation. Only a few vasoactive substances were known
at the time: norepinephrine, epinephrine, and angiotensin. By the year
2000, a myriad of molecules with vasoactive properties had been
discovered. The endogenous vasoconstrictors include endothelin,
leukotriene, serotonin, thromboxane, etc; the vasodilators include NO,
natriuretic peptide, prostaglandin E, and prostacyclin, to name a few.
The paradigm of 1950 was that the contractile tone was under
neuroendocrine control. We now realize that many of the vasoactive
substances are synthesized locally within the vessel wall, thereby
exerting autocrine and paracrine effects. The receptors and
intracellular signaling pathways mediating the actions of these
vasoactive substances have, in large part, been characterized, as noted
above. With the introduction of molecular biological techniques, most
of the genes encoding the vasoactive peptides, the processing enzymes,
and the receptors have been cloned and genetically studied. As a
result, our understanding of systemic, regional, and local control of
vasomotor tone is much improved, and the pathophysiological role of the
imbalance of these factors in cardiovascular diseases such as
hypertension, angina, and congestive heart failure has been elucidated.
An important outcome of these advances is the discovery of drugs that
target these vasoactive substances, their actions, their synthesis, and
cellular pathways that have yielded effective therapy for these
disorders. These included ACE inhibitors, as discussed earlier;
angiotensin (AT1) receptor antagonists; calcium
channel blockers; 
- and ß-blockers; and more recently, leukotriene
antagonists and possibly endothelin antagonists in the near future, to
name a few. For these accomplishments and others in related areas, the
Nobel Prize in Medicine and Physiology was awarded in 1982 to
Bergstrom, Samuelsson, and Vane for their discoveries of prostanoids;
in 1988 to Black, Elion, and Hitchings for synthesis of ß-blockers;
and in 1998 to Furchgott, Ignaro, and Murad for their discoveries of NO
and its function.
In addition to contractile function, the vascular smooth muscle has been shown to be a pleiotropic cell capable of phenotypic changes associated with the synthesis of many biologically active molecules that mediate cell growth, death, and migration, as well as matrix modulation and inflammation. These actions of vascular smooth muscle play important roles in physiological vascular functions, such as vascular remodeling, and in pathological disorders, such as atherosclerosis, restenosis, transplant vasculopathy, and other vascular diseases. A cadre of endogenous biological mediators regulating smooth muscle phenotype and function has been identified; none of these were known to exist 50 years ago. These molecules, commonly synthesized in the vessel wall, include growth factors, proapoptotic factors, matrix glycoproteins, metalloproteinases, cytokines, chemokines, and adhesion molecules.
The ability of the blood vessel to adapt to and accommodate long- and short-term changes in flow is a critical function in cardiovascular homeostasis.28 In addition to the short-term changes in vasomotor tone in response to alterations in shear stress mediated by release of vasoactive substances, eg, NO, by the endothelium, long-term adaptive responses to sustained alterations in physiological or pathophysiological conditions are dependent primarily on changes of vascular structure. Earlier, Glagov proposed that atherosclerotic arteries could remodel structurally to maintain an adequate lumen. This concept was derived from careful morphological analysis of human atherosclerotic arteries. It is now known that active remodeling of the blood vessel involves cell growth or apoptosis, extracellular matrix expansion or contraction, and activation or inhibition of specific proteolytic enzymes or glycosidases. This remodeling response is usually a long-term adaptive process occurring in response to chronic changes in hemodynamic conditions. Abnormal or pathological remodeling in conditions such as hypertensive vascular hypertrophy, atherosclerosis, bypass graft disease, restenosis, and transplant vasculopathy involves inappropriate cellular and extracellular changes leading to narrowing or occlusion of the lumen. Thus, much progress has been made in the past 5 decades in the understanding of the fundamental importance of vascular remodeling in cardiovascular homeostasis and of the complex biological processes mediating physiological and pathological remodeling.
Angiogenesis
An area of vascular biology that has potentially
significant clinical impact is angiogenesis. The generation of new
blood vessels is central to the pathogenesis of certain disease
processes, such as diabetic retinopathy, tumorigenesis, and chronic
tissue ischemia. Indeed, 5 decades ago, the pathologists were well
aware of the existence of excess collateral vessels in the myocardium
associated with advanced coronary artery disease. Subsequently,
angiographic techniques documented the importance of collaterals in
ischemic heart disease. New vessels are formed in response to vascular
occlusion to provide collateral flow as well as after myocardial
infarction as part of the wound-healing response. During the past 2
decades, the cellular process of angiogenesis has been elucidated and
families of molecules that mediate angiogenesis have been identified,
as well as their receptors and intracellular signaling
pathways.29 The
emerging field of therapeutic angiogenesis holds promise for the
treatment of ischemic disorders through increased angiogenesis and for
conditions of pathological angiogenesis (through the inhibition of
angiogenesis) such as neoplasm and diabetic
retinopathy.30
Impact of Vascular Biology on Clinical Medicine
The most important contribution of vascular biology is in the treatment of cardiovascular diseases.31 32 During the past 50 years, we have witnessed major transformation in the diagnosis and therapy of coronary artery disease, hypertension, and congestive heart failure. As we gain understanding of the mechanisms regulating vascular tone, hemostasis, thrombosis, and inflammation and of the pathobiology of acute ischemic syndromes, plaque pathology, and pathological remodeling, the new knowledge has been applied to the clinical arena. Indeed, diagnostic tools such as angiography, intravascular ultrasound, angioscopy, and nuclear imaging and MRI were developed in parallel with the information derived from vascular biology research. The expanded knowledge has also resulted in the development of effective therapeutics such as drugs, devices, and surgery. The future holds much promise for the development of novel therapies such as small molecule, antisense oligonucleotides, transcriptional factor decoys, protein therapy, gene therapy, cell-based therapy, and gene, cell, or tissue engineering. The interface of genetic or molecular technologies with devices or surgery is particularly exciting. It is important to note that proofs of concept in several areas have already been demonstrated by a number of laboratories.
Vascular biology successfully brought together basic scientists and clinical investigators. It stimulated interactions and collaborations among researchers from multiple disciplines and developed new training opportunities. From these activities emerged the discipline of vascular medicine.31 This trend has been fostered by the American Heart Association, the American College of Cardiology, and the National Institutes of Health. In the 1990s, the National Heart, Lung, and Blood Institute initiated a request for applications for Program Projects to develop centers of Vascular Biology and Medicine, as well as Academic Awards in Systemic and Pulmonary Vascular Disease. The American College of Cardiology formed the vascular disease committee to examine training and practice in this area. The American Heart Association, recognizing the importance of this field, developed an intercouncil vascular biology working group that eventually merged with the Council of Arteriosclerosis and the Thrombosis Council to form a new Council of Arteriosclerosis, Thrombosis, and Vascular Biology in 1996. Thus, from modest beginnings, vascular biology has grown and matured over the past 50 years to be a major factor in cardiovascular science and medicine.
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