Braunwald's Heart Disease: A Textbook of Cardiovascular
Medicine, 8th ed CHAPTER 38 – The Vascular Biology of Atherosclerosis
STRUCTURE OF THE NORMAL ARTERY
The Cell Types That Comprise the Normal Artery
Endothelial Cells
The endothelial cell of the arterial intima constitutes the crucial contact surface with
blood. Arterial endothelial cells possess many highly regulated mechanisms of capital
importance in vascular homeostasis that often go awry during the pathogenesis of
arterial diseases.[4] For example, the endothelial cell provides one of the only surfaces,
either natural or synthetic, that can maintain blood in a liquid state during protracted
contact ( Fig. 38-2 ). This remarkable blood compatibility derives in part from the
expression of heparan sulfate proteoglycan molecules on the surface of the endothelial
cell. These molecules, like heparin, serve as a co-factor for antithrombin III, causing a
conformational change that allows this inhibitor to bind to and inactivate thrombin.
The surface of the endothelial cell also contains thrombomodulin, which binds
thrombin molecules and can exert antithrombotic properties by activating proteins S
and C. Should a thrombus begin to form, the normal endothelial cell possesses potent
fibrinolytic mechanisms associated with its surface. The endothelial cell can produce
both tissue and urokinase-type plasminogen activators. These enzymes catalyze the
activation of plasminogen to form plasmin, a fibrinolytic enzyme. (For a complete
discussion of the role of endothelium in hemostasis and fibrinolysis, see Chap. 82 ).
FIGURE 38-2 The endothelial thrombotic balance. This diagram depicts the anticoagulant profibrinolytic functions
of the endothelial cell (left) and certain procoagulant and antifibrinolytic functions (right). HSPG = heparan sulfate
proteoglycan; PAI-1 = plasminogen activator inhibitor-1; PGI 2 = prostacyclin; tPA = tissue type plasminogen
activator; uPA = urokinase type plasminogen activator; vWf = von Willebrand factor.
Endothelial cells have a common origin but acquire bed-specific characteristics
during development. The endothelial cells that form the inner lining of all blood
vessels arise during embryogenesis from regions known as the blood islands,
located on the embryo's periphery. Angioblasts, the predecessors of the endothelial
cells, share this site with the precursors of blood cells. Despite arising from the
same site, cells display considerable heterogeneity even during embryological and
early postnatal development. Although endothelial cells presumably derive from a
common precursor, the signals they encounter during vessel development differ. As
rudimentary blood vessels begin to form, endothelial precursors interact with
surrounding cells. The interchange permits spatial and temporal gradients of
various stimuli and their receptors on the endothelial cells, leading to this cell
type's heterogeneity in the adult. Endothelial cell heterogeneity depends on both
environmental stimuli and epigenetic features acquired during development.[5]
Recent evidence has indicated that the cells that make up various compartments of
the arterial wall can originate from bone marrow during postnatal life as well as
from their traditional embryological sources. In particular, peripheral blood appears
to contain endothelial precursor cells that may help the repair of areas of
endothelial desquamation. Moreover, in injured or transplanted arteries, smooth
muscle cells of apparent bone marrow origin can take up residence in the intima or
media (see later). The endothelial progenitor cells (EPCs) bear characteristic
markers such as CD133, CD34, and vascular endothelial growth factor receptor-2.
Circulating numbers of EPCs, as assayed in vitro, vary among individuals. Those
with a higher burden of risk factors for atherosclerosis have fewer EPCs. EPC
number may correlate with prognosis in atherosclerotic patients.[6] More aged
individuals may have impaired EPC numbers and hence less ability to repair
breaches in intimal integrity.[7]
Differential expression of endothelial genes in various types of blood vessels
depends on transcriptional regulation by the local environment. For example, the
promoter region of the gene that encodes von Willebrand factor directs expression
in the endothelium of brain and heart microvessels but not in larger arteries. Co-
culture of endothelial cells with cardiac myocytes, but not other cell types, could
selectively activate a von Willebrand factor gene promoter construct. Likewise,
endothelial nitric oxide synthase gene activity in the heart shows bed-specific
regulation. Members of the EPH family of tyrosine kinase receptors and their
ligands, known as ephrins, display heterogeneous expressions in arterial versus
venous endothelial cells during development. In the adult, arterial endothelial and
SMCs, but not venous vascular cells, express ephrinB2. This finding supports a
stable lineage difference between cells that make up arteries and veins. These
examples illustrate the molecular diversity of cell location in the circulation.[8]
Phage display and proteomic techniques have begun to substantiate the in vivo
significance of vascular cell heterogeneity in atherogenesis.[9]
Arterial Smooth Muscle Cells
The second major cell type of the normal artery wall, the smooth muscle cell (SMC)
has many important functions in normal vascular homeostasis, as a target of therapies
in cardiovascular medicine, and in the pathogenesis of arterial diseases. These cells
contract and relax and thus control blood flow through the various arterial beds,
generally at the level of the muscular arterioles. In the larger types of arteries involved
in atherosclerosis, however, abnormal smooth muscle contraction may cause
vasospasm, a complication of atherosclerosis that may aggravate the embarrassment
of blood flow. SMCs synthesize the bulk of the complex arterial extracellular matrix
that plays a key role in normal vascular homeostasis as well as the formation and
complication of atherosclerotic lesions. These cells also can migrate and proliferate,
contributing to the formation of intimal hyperplastic lesions including atherosclerosis
and restenosis or in stent stenosis following percutaneous interven-tion, or
anastomotic hyperplasia complicating vein grafts. Death of SMC may promote
destabilization of atheromatous plaques or favor ectatic remodeling and ultimately
aneurysm formation.
In contrast to endothelial cells thought to derive from a common precursor, SMC
can arise from many sources. After endothelial cells form tubes, the rudimentary
precursor of blood vessels, they recruit the cells that will become smooth muscle,
or pericytes (smooth muscle-like cells associated with microvessels). In the
descending aorta and arteries of the lower body, the regional mesoderm serves as
the source of smooth muscle precursors. The mesodermal cells in somites give rise
to the SMCs that invest much of the distal aorta and its branches. In arteries of the
upper body, however, SMCs can actually derive from a completely different germ
layer, neurectoderm rather than mesoderm. Before the neural tube closes,
neurectodermal cells migrate and become the precursors of SMCs in the ascending
aorta and some of its branches, including the carotid arteries ( Fig. 38-3 ). SMCs in
the coronary arteries derive from mesoderm, but in a special way. The precursors
of coronary artery SMCs arise from yet another embryological source, a structure
known as the proepicardial organ.
As in the case of endothelial cells, SMCs show molecular heterogeneity early
during development. [10] [11] [12] For example, the promoter of a characteristic smooth
muscle gene, known as SM22, drives gene expression in venous, but not arterial,
SMCs during embryogenesis. A specific transcription factor known as dHAND
signals the recruitment of mesenchyme by endothelial cells in an anatomically
heterogeneous manner during development. In particular, dHAND regulation
participates selectively in recruitment of mesenchyme in upper body blood vessels
versus those of the more caudal portions of the embryo. A CArG box-dependent
enhancer within the regulatory regions of the cysteine-rich protein 1 gene directs
this protein's expression in arterial, but not venous or visceral, SMCs. Differential
dependence on CArG elements in the control of SMC gene transcription furnishes
a molecular basis for SMC heterogeneity in different arterial beds.[12] These
findings illustrate molecular distinctions between the cells that comprise different
types of vessels.
FIGURE 38-3 Left, Anterior view of an embryonic chick heart in which cells of neural crest origin stain blue.
Note the focal localization of cells derived from neural crest in the great arteries as well as the cardiac
innervation plexus spread over the ventricles. Ao = aorta; BA = brachiocephalic artery; PT = pulmonary trunk;
RA = right atrium; RV = right ventricle. Bar = 750μm. Right, Posterior view of a chicken embryo heart-lung
whole-mount similarly tagged. Note the sharp demarcation in the localization of the blue neural crest-derived
cells in the aortic arch (AoAr) and dorsal aorta (DA) before they unite to form the descending aorta (DsAo). The
arrowhead indicates neural crest-derived neural tissue. LL and RL indicate left and right lung, respectively. Bar
= 250μm. (From Bergwerff M, Verberne ME, DeRuiter MC, et al: Neural crest cell contribution to the
developing circulatory system. Circ Res 82:221, 1998.)
The Intima
Understanding the pathogenesis of atherosclerosis first requires knowledge of the
structure and biology of the normal artery as well as its indigenous cell types. Normal
arteries have a well-developed tri-laminar structure ( Fig. 38-4 ). The innermost layer,
the tunica intima, is thin at birth in humans and many nonhuman species. Although
often depicted as a monolayer of endothelial cells abutting directly on a basal lamina,
the structure of the adult human intima is actually much more complex and
heterogeneous. The endothelial monolayer resides on a basement membrane
containing nonfibrillar collagen types, such as type IV collagen, laminin, fibronectin,
and other extracellular matrix molecules. With aging, human arteries develop a more
complex intima containing arterial SMCs and fibrillar forms of interstitial collagen
(types I and III). The SMC produces these extracellular matrix constituents of the
arterial intima. The presence of a more complex intima, known by pathologists as
diffuse intimal thickening, characterizes most adult human arteries. Some locales in
the arterial tree tend to develop thicker intimas than other regions, even in the absence
of atherosclerosis ( Fig. 38-5 ). For example, the proximal left anterior descending
coronary artery often contains an intimal cushion of SMCs more fully developed than
that in typical arteries. The diffuse intimal thickening process does not necessarily go
hand in hand with lipid accumulation, and may occur in individuals without
substantial burden of atheroma. The internal elastic membrane bounds the tunica
intima abluminally, and serves as the border between the intimal layer and the
underlying tunica media.
FIGURE 38-4 The structures of normal arteries. A, Elastic artery. Note the concentric laminae of elastic tissue that
form sandwiches with successive layers of smooth muscle cells (SMCs). Each level of the elastic arterial tree has a
characteristic number of elastic laminae. B, Muscular artery. The muscular artery, the SMCs, are surrounded by a
collagenous matrix but lack the concentric rings of well-organized elastic tissue characteristic of the larger arteries.
FIGURE 38-5 An intimal cushion shown in a cross-section through the internal carotid artery of a 10-week-old
male infant. Areas where intimal cushions form in early life tend to develop atheromas more commonly in later
years. The bar shows 0.5μm. (From Weniger WJ, Muller GB, Reiter C, et al: Intimal hyperplasia of the infant
parasellar carotid artery: A potential developmental factor in atherosclerosis and SIDS. Circ Res 85:970, 1999.)
The Tunica Media
The tunica media lies under the media and internal elastic lamina. The media of
elastic arteries such as the aorta have well-developed concentric layers of SMCs,
interleaved with layers of elastin-rich extracellular matrix (see Fig. 38-4A ). This
structure appears well adapted to the storage of the kinetic energy of left ventricular
systole by the walls of great arteries. The lamellar structure also doubtless contributes
to the structural integrity of the arterial trunks. The media of smaller muscular arteries
usually have a less stereotyped organization (see Fig. 38-4B ). SMCs in these smaller
arteries generally embed in the surrounding matrix in a more continuous than lamellar
array. The SMCs in normal arteries seldom proliferate. Indeed, rates of both cell
division and cell death are quite low under usual circumstances. In the normal artery,
a state of homeostasis of extracellular matrix also typically prevails. Because
extracellular matrix neither accumulates nor atrophies, rates of arterial matrix
synthesis and dissolution usually balance each other. The external elastic lamina
bounds the tunica media abluminally, forming the border with the adventitial layer.
The Adventitia
The adventitia of arteries has typically received little attention, although appreciation
of its potential roles in arterial homeostasis and pathology has recently increased. The
adventitia contains collagen fibrils in a looser array than is usually encountered in the
intima. Vasa vasorum and nerve endings localize in this outermost layer of the arterial
wall. The cellular population in the adventitia is more sparse than in other arterial
layers. Cells encountered in this layer include fibroblasts and mast cells (see Fig. 38-4
). Emerging evidence suggests a role for mast cells in atheroma and aneurysm
formation in animal models, but their importance in humans remains speculative.
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