From the Cardiovascular Institute (V.F.), Mount Sinai Medical Center, New
York, NY; Cardiovascular Institute, Mount Sinai Medical Center, New York
(M.P.); and St. Luke's Episcopal Hospital/Texas Heart Institute
(J.T.W.), Houston, Tex.
Correspondence to Valentin Fuster, MD, PhD, Director, Cardiovascular Institute, Mount Sinai Medical Center, 1 Gustave Levy Place, Box 1030, New York, NY 10029-6574. E-mail Valentin_Fuster{at}smtplink.mssm.edu
Vascular
remodeling plays an important role in the development of native
atherosclerosis and restenosis after PTCA. A
typical atherosclerotic plaque consists of a core of lipid-rich
macrophages surrounded by a thickened intima under the cover of
a fibrous cap. Endothelial cell injury, related to
shear forces and modified by certain risk
factors,1 appears to be a critical initial event
in atherogenesis. The surface of dysfunctional
endothelium serves as a point of entry for circulating
inflammatory cells, such as lymphocytes and monocytes. The recruitment
of circulating monocytes and subsequent transmigration of monocytes
through the dysfunctional endothelium require the
careful orchestration of circulating and secreted factors and various
cellular components found in the circulation and the vessel wall.
Cell adhesion molecules have emerged as essential factors in the
development of atherosclerosis and restenosis.
In particular, P-selectin has been established as an important marker
of chronic and acute atherosclerotic events. P-selectin is present
in the
Clinically, many studies have demonstrated that elevated plasma levels
of soluble P-selectin have been associated with heightened vascular
activity in both acute and chronic coronary atherosclerotic
diseases. Increased plasma levels of P-selectin in patients with stable
coronary artery disease before elective PTCA have been shown to
correlate with both an increased risk of acute ischemic events
within the first 24 hours after PTCA6 and an
increased rate of restenosis within 6
months.7 The immediate surface expression of
P-selectin and glycoprotein IIb/IIIa in activated
platelets of blood drawn from the coronary sinus was
maximal at 5 minutes after PTCA, and this expression was significantly
inhibited by infusion of S-nitrosoglutathione, a potent donor of nitric
oxide, 10 minutes before the PTCA.8 Plasma levels
of P-selectin were significantly elevated after unstable angina but
were unchanged after exertional angina in patients with chronic stable
coronary disease.9 10 In addition,
elevated circulating levels of P-selectin have been shown to be a
reliable marker of chronic atherosclerosis. Patients
with chronic ischemic heart disease and peripheral
vascular disease have significantly higher levels of soluble P-selectin
than age- and sex-matched asymptomatic healthy control
subjects.11 Interestingly, Karlheinz et
al12 reported that the extent of human
atherosclerosis seemed to correlate with circulating
levels of vascular cell adhesion molecule-1 but not with P-selectin,
E-selectin, ICAM-1, or thrombomodulin. In addition, levels of soluble
P-selectin in patients with peripheral artery disease
correlated with levels of ß-thromboglobulin, a
marker of platelet activation, but failed to correlate with levels
of either von Willebrand factor or soluble thrombomodulin, both
of which are markers of endothelial cell
dysfunction.13 In contrast, patients with chronic
hypertension have been shown to have an elevation of both P-selectin
and von Willebrand factor levels, and the levels correlated
with elevation in diastolic
pressure.14 This apparent difference in the
pattern of markers of platelet and endothelial cell
activity in peripheral vascular disease and chronic
hypertension may provide important leads for future investigation,
which may result in a better understanding of the interactions between
various cell adhesion molecules and their pathogenic roles in chronic
atherosclerotic processes.
The use of transgenic animal models has become a powerful
investigative tool for a better understanding of the genetic cause of
various diseases. The transgenic mouse is a particularly useful and
popular model because its genome is very well characterized and can be
manipulated with relative ease. The general approach is to introduce
genetically engineered material into very young embryos that are
subsequently reimplanted into foster mothers. The genetic material
introduced in the engineered mouse can then be regulated to either
overexpress or underexpress certain specific gene products at
various stages of the animal's life, and the effect on the
phenotype can be studied. The use of transgenic mouse models in
the study of atherosclerosis and
hyperlipidemia has been well established (see review by
Paigen et al15 ). Various forms of selectin ko
mice have also been generated (see review by Frenette and
Wagner16 ). P-selectin ko mice have a prolonged
bleeding time and a major defect of leukocyte rolling, adding
additional support to the concept that P-selectin may play a key role
in hemostasis and in acute inflammatory response and wound repair.
P-selectin has been shown to play an important role in the recruitment
of lymphocytes to lymph nodes by facilitating the rolling of
lymphocytes on platelet-activated
endothelium.17 Double ko of
P-selectin and E-selectin mice have severe leukocytosis, which is
absent in single-selectin ko mice, suggesting that both selectins are
important for maintaining leukocyte homeostasis. To examine the role of
P-selectin in the development of fatty streaks in an LDLR-deficient
mouse, which has been shown to develop an atherosclerotic lesion when
fed a high-fat diet for 8 weeks, Johnson et al18
crossed a P-selectin ko mouse with an LDLR-deficient mouse. The male
offspring had a twofold reduction in atherosclerotic lesion size in the
cusp region of the aorta compared with P-selectin–positive mice,
demonstrating the importance of P-selectin in the early development of
atherosclerosis. Preliminary data from a triple ko of
P-selectin, E-selectin, and LDLR demonstrated the persistent reduction
of the lesion size after 22 weeks on the same high-fat diet. Thus,
these transgenic studies strongly support the hypothesis that the
selectins are crucial for the binding of monocytes to dysfunctional
endothelium and for the binding of activated
platelets to monocytes and the endothelium, two of
the critical initiating events in
atherogenesis.16
In spite of the abundance of valuable information gained from various
studies that used transgenic mice, this model has not been as popular
and successful for the study of vascular injury and restenosis
because of the technical difficulty in inducing vascular injury by
endothelial denudation in these small animals.
Investigators have developed ingenious methods of injuring the vessels
in an attempt to mimic certain aspects of vascular response after
injury. Carmeliet et al19 pioneered the use of
perivascular electric injury in the femoral arteries of transgenic
mice. In this model, severe injury to the vessel was created by
delivering an electric current to a segment of the vessel, resulting in
complete destruction of the medial smooth muscle cells, denudation of
the injured segment of intact endothelium, and
transiently induced platelet-rich mural thrombosis. There was
subsequent infiltration of inflammatory cells and progressive removal
of the mural thrombus and necrotic debris after the injury. In a
separate study,20 the same investigators induced
the same type of injury in plasminogen-deficient mice and
found that the wound healing process was significantly impaired in the
plasminogen-deficient mice, with delayed removal of
necrotic debris, reduced leukocyte infiltration, and smooth muscle cell
migration into the necrotic center. Compared with human
atherosclerosis, this model may be overly severe and
physiologically irrelevant. Nevertheless, it
may be a useful tool with which to study the genetic basis of vascular
wound healing.
Another model of vascular injury in transgenic mice was recently
reported by Kumar et al21 in which the common
carotid artery was ligated at the bifurcation, resulting in significant
neointimal formation in the presence of an
endothelialized artery. Although this model may be
criticized for being artificial and
unphysiological, it provides unique insights in
that there was very little thrombus formed at the site of occlusion,
possibly because of the presence of an intact
endothelium at the site of injury. There was an initial
loss of smooth muscle cells from the media 2 days after ligation,
followed by intimal hyperplasia of smooth muscle cells in the intima,
with maximal response detected at 2 weeks. There was also an early
inflammatory response with an increased infiltration of leukocytes in
the developing intima and near the luminal surface. The inflammatory
response became undetectable at 4 weeks after ligation. This model
provides a unique opportunity for genetic study of the interaction
between leukocytes and endothelial cells without the
presence of circulating platelets, a potentially confounding
factor. In a previous issue of
Circulation,22 Kumar et al applied
this carotid artery injury model to the study of the role of P-selectin
in the early remodeling and neointimal formation of normal
and P-selectin–deficient mice. The left common carotid artery was
ligated in P-selectin–deficient and normal mice. The animals were
killed in two groups. The first group of animals were killed at 4 weeks
after ligation for evaluation of lesion formation. Significant
reduction of the neointimal and medial area ratios was
found in the P-selectin mice compared with the normal controls. A
second group of animals were killed at 3 and 7 days after ligation for
evaluation of the inflammatory leukocytes present in the developing
lesions. In the P-selectin mice, there was a significant reduction of
the inflammatory cells present in the developing lesions at day 7
after ligation in spite of a 49% increase of total leukocyte counts in
the P-selectin mice versus normal mice. This study further affirms the
importance of P-selectin in the cellular interactions between
circulating leukocytes and endothelium and in the
recruitment of circulating leukocytes into the vessel wall after
injury.
Molecular mechanisms that underlie the sexual difference in the
development of human atherosclerosis have been an
important area of cardiovascular research. Emerging
experimental evidence suggests a possible link between estrogen and its
effect on cell adhesion molecules. In women, cyclic variation in serum
estradiol levels has been associated with the maximal decrease of serum
P-selectin levels in the luteal phase. A single intramuscular injection
of 17ß-estradiol also significantly lowered soluble P-selectin levels
in healthy male volunteers, with maximal reduction occurring on day 5
after injection. Research using transgenic mice has also lent important
support for the crucial role of estrogen in atherogenesis. Not unlike
humans, female LDLR- and combined LDLR and P-selectin–deficient mice
have recently been shown to be less susceptible to diet-induced
atherosclerosis.18 Thus, the
transgenic mouse appears to be an ideal model for future studies of the
genetic basis of various cellular adhesion molecules in
atherogenesis.
Selected Abbreviations and Acronyms
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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© 1998 American Heart Association, Inc.
Editorials
Learning From the Transgenic Mouse
Endothelium, Adhesive Molecules, and Neointimal Formation
Key Words: endothelium • plaque • genes
-granules of inactivated platelets and in the
Weibel-Palade bodies of endothelial cells. It is
quickly redistributed to the surface of platelets and
endothelial cells in response to activation by
agonists, such as thrombin.2 Increased expression
of P-selectin and ICAM-1 has been shown in endothelium
overlying atherosclerotic plaques but not in normal
arterial endothelium or in
endothelium overlying inactive fibrous plaques from the
carotid and coronary arteries of postmortem specimens and
patients undergoing vascular surgery.3 Poston and
Johnson-Tidey4 further demonstrated that
anti–P-selectin antibody blocks the in vitro binding of monocytes to
the endothelium but not to the denuded intima of
atherosclerotic arteries, demonstrating the importance of P-selectin as
a major adhesive molecule for monocyte binding to the
endothelium. P-selectin has been shown to be
upregulated in both acute and chronic rejection in the rat cardiac
allograft arteriosclerosis model. In this model,
the expression of P-selectin is correlated with the intensity of
intimal thickening.5
ICAM-1
=
intercellular adhesion molecule-1
ko
=
knockout(s)
LDLR
=
LDL receptor
PTCA
=
percutaneous transluminal coronary
angioplasty
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