EVE and beyond, retro and prospective insights
Marlene
Rabinovitch
Division of Cardiovascular Research, Hospital for Sick Children,
Toronto, Ontario, Canada M5G 1X8
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ABSTRACT |
Our work has focused on the discovery that an
endogenous vascular elastase (EVE) plays a pivotal role in the vascular
changes associated with the development and progression of pulmonary
hypertension. Recent studies have identified serum factors that
stimulate transcription of this enzyme and have elucidated a signal
transduction process involving activation of the mitogen-activated
protein kinase pathway and nuclear expression of the transcription
factor AML1. Proteases release and activate growth factors that are
bound to the extracellular matrix and also induce, in a
3-integrin-dependent manner,
the transcription of the gene for the matrix glycoprotein tenascin. Tenascin alters smooth muscle cell shape and facilitates the
proliferative response to growth factors by clustering and activating
growth factor receptors. In addition, breakdown products of elastin, elastin peptides, can upregulate the production of fibronectin, a
glycoprotein that is critical to smooth muscle cell migration. The
mechanisms regulating enhanced fibronectin production have recently
been successfully targeted to prevent the development of intimal lesions.
endogenous vascular elastase; pulmonary hypertension; extracellular matrix; elastase; tenascin; fibronectin
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INTRODUCTION |
OUR STUDIES began with EVE (endogenous vascular
elastase). Like all mother figures, EVE likely has an important
nurturing function suggested by the fact that the enzyme is expressed
in the embryo at sites of vascular remodeling. Like the biblical Eve,
however, the enzyme also has a darker side in that once reactivated in
response to injury, it stimulates a zealous and misdirected remodeling
that thickens the vessel wall and occludes the lumen.
EVE is a 20-kDa enzyme related to the serine proteinase adipsin
(34). If there is an EVE, there must also be an Adam, and, indeed, the naturally occurring partner for EVE appears to be elafin, a
9-kDa serine elastase inhibitor first found in skin and bronchial
secretions but also expressed in embryonic and postnatal vessel walls,
accompanying and likely modulating the activities of EVE (21, 25, 26).
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EVE AND PULMONARY VASCULAR DISEASE: AN OVERVIEW |
Our evidence that EVE was important in the pathophysiology of pulmonary
vascular disease was first suggested by electron-microscopic studies in which we showed fragmentation of elastin as an early feature
of pulmonary vascular lesions in patients with congenital heart defects and left to right shunts (24). We measured an increase in serine elastase activity in the pulmonary
arteries (PAs) of rats in which pulmonary hypertension was induced by
exposure to hypoxia (15) or after injection with the toxin
monocrotaline (29, 31). A cause-and-effect relationship was
demonstrated in studies in which we showed that elastase inhibitors
prevented pulmonary hypertension and associated vascular disease or
greatly retarded its progression (15, 31).
Studies have been carried out in cultured endothelial and
smooth muscle cells (SMCs) to investigate how pulmonary
hypertension-producing stimuli such as the high flow and pressure of a
congenital heart defect, hypoxia, or toxins might induce structural
changes in PAs (Fig. 1). We reasoned that
the structural and functional alterations in the endothelium (24) would
result in loss of barrier function. This would, as a consequence, allow
penetration into the subendothelium of a serum factor that could
stimulate SMC production and the release of EVE. The idea that EVE
could come from SMCs was predicated on the observations of the French
investigators Hornebeck et al. (10), who first
demonstrated activity of a serine elastase in cultured SMCs and in
atherosclerotic tissues.

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Fig. 1.
Schema showing proposed role of elastase in pathogenesis of pulmonary
vascular disease. EVE, endogenous vascular elastase; SMC, smooth muscle
cell; bFGF, basic fibroblast growth factor-2; TGF- , transforming
growth factor- .
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Our studies (14, 27) have, in fact, shown that SMCs in culture degrade
radiolabeled elastin when stimulated with serum- or
endothelial-conditioned medium (Fig. 2).
This is coupled with increased adhesion of radiolabeled elastin to the
cell surface. In fact, pretreating elastin or cells with serum- or with
endothelial-conditioned medium was as effective as serum alone and
appeared to accelerate elastin degradation. The elastin binding
elastase-inducing serum component appears to be, at least in part,
attributed to apolipoprotein A1. The mechanism involves tethering
elastin to the SMC surface and engaging it directly with the elastin
binding protein. Tyrosine kinase-mediated intracellular signaling is
induced, resulting in transcription of mRNA. There is increased
expression of the transcription factor AML1, discovered by PCR
differential display (30). AML1 is critical in white cell
differentiation (a mutation causes acute myelogenous leukemia) and also
has a recognition site in the promoter of neutrophil elastase (22),
making it a likely candidate as a transcription factor for EVE
(27).1

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Fig. 2.
Serum induction of elastolytic activity in fetal lamb pulmonary artery
(PA) SMCs. Values are means ± SE of increase in elastolytic
activity over that under serum-free conditions (i.e., 0.1% BSA) from 3 separate assays. There was significant elastolysis with a fetal bovine
serum (FBS) concentration of only 0.1%
(* P < 0.05 compared with
serum-free condition), and maximum activity was evident with a
concentration of 1% FBS, with no further increase observed with 5 or
10% FBS (** P < 0.01 compared
with serum-free condition). (Reproduced from J. Kobayashi, D. Wigle, T. Childs, L. Zhu, F. W. Keeley, and M. Rabinovitch.
Journal of Cellular Physiology 160:
121-131, 1994. Copyright 1994, John Wiley & Sons, Inc. Reprinted
by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons,
Inc.)
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EVE is a powerful enzyme that, by virtue of its ability to degrade
elastin, will also degrade proteoglycans that serve as storage sites
for growth factors, such as basic fibroblast growth factor (FGF-2) and
transforming growth factor-
. A study from our laboratory (28) has
shown that EVE releases FGF-2 in a biologically active form that
stimulates SMC proliferation (Fig. 3).

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Fig. 3.
EVE-mediated release of 125I-bFGF
into conditioned medium. Serum-starved ovine PASMCs preincubated with
125I-bFGF were exposed to
serum-pretreated elastin (STE). STE treatment resulted in a
concentration-dependent release of
125I-bFGF into conditioned medium.
cpm, Counts/min. Values are means ± SD from 1 of 2 independent
experiments with similar significance
(* P < 0.05 compared with
control levels). (Reproduced from K. Thompson and M. Rabinovitch.
Journal of Cellular Physiology 166:
495-505, 1996. Copyright 1996, John Wiley & Sons, Inc. Reprinted
by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons,
Inc.)
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Elastase activity either directly or via activation of matrix
metalloproteinases can induce production of the matrix glycoprotein tenascin (TN) (17), which optimizes the mitogenic response to FGF-2 and
is, in fact, a prerequisite for the response to epidermal growth factor
(EGF) in cultured SMCs (13).
The process of SMC migration also appears to depend, at least in
experimental animals, on the continued activity of elastase. We (7, 9)
have shown that elastin peptides stimulate the production of the matrix
glycoprotein fibronectin (FN), which changes SMCs from a contractile to
a migratory phenotype, and we have begun to unravel a unique molecular
mechanism of regulation.
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TN AND THE VASCULAR SMC PROLIFERATIVE RESPONSE |
We pursued the expression of TN in vascular disease by carrying out
immunohistochemical analyses in biopsy tissue from patients with
congenital heart defects. Minimal expression of TN was apparent with
mild disease, but with progressive hypertrophy, intense foci were
observed in the adventitia, periendothelium, and, occasionally, the
media. With the development of obstructive lesions, TN colocalized in
the neointima, with increased expression of EGF and proliferating cells
as judged by positive immunostaining with an antibody that recognizes
the proliferating cell nuclear antigen (11) (Fig. 4). A similar relationship was seen in the
evolution of experimental pulmonary vascular disease. TN was apparent
in the adventitia and outer media in PAs from rats 14 days after
injection of monocrotaline, coincident with the development of
pulmonary hypertension, and in the inner media and emerging neointima
by day 21, associated with progressive
disease and colocalization with proliferating cells. The morphological
expression of TN is coupled with evidence of the induction of TN mRNA
transcripts by Northern blot analysis (Fig.
5). Cultured rat SMCs showed that TN
augmented the proliferative response to FGF-2 and was a prerequisite
for the proliferative response to EGF (Fig.
6). The mechanism appears to
involve a TN-mediated change in the cytoskeleton such that when TN is
engaged by its integrin
(
v
3),
actin filaments rearrange in focal adhesion contacts and EGF receptors
are clustered and primed. The addition of EGF results in rapid
phosphorylation of the EGF receptor and a cascade of phosphorylation
events that results in a nuclear signal necessary for mitosis (12)
(Fig. 7). On the other hand, complete
withdrawal of TN results in SMC apoptosis.

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Fig. 4.
Representative photomicrographs showing immunoperoxidase staining for
tenascin (TN)-C (A,
D, and
G), proliferating cell nuclear
antigen (PCNA; B,
E, and
H), and epidermal growth factor
(EGF; C,
F, and
I) in graded lung biopsy tissue
sections.
A-C:
vessel showing a typical grade IA
lesion.
D-F:
vessel showing a typical grade IC
lesion.
G-I:
vessel showing a typical grade
IIIC lesion. In low-grade lesions
(A), modest TN immunostaining was
evident in adventitia. With medial hypertrophy, TN immunoreactivity
became more prominent in periendothelium
(D), with the most intense
immunostaining being apparent within neointima of high-grade lesions,
showing occlusive neointimal formation
(G). In lowest grade of lesion, PCNA
was negative (B) despite foci of EGF
in media. With medial hypertrophy, PCNA was expressed in media
(E) together with foci of EGF
(F). With development of
higher-grade occlusive lesions, TN
(G), PCNA
(H), and EGF
(I) colocalized to neointimal cell
layers. Note that TN and PCNA staining was performed on serial
sections, whereas EGF detection was carried out on similar vessels
within the same biopsy. Original magnification, ×40.
[Reproduced with permission from Jones et al. (11).]
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Fig. 5.
Northern blot analyses for TN in adult PA
(A,
top) and lung
(A,
bottom) tissue isolated at 7 (7d),
14 (14d), and 28 days (28d) post-monocrotaline injection. Two TN
isoforms of ~6.4 and 7.3 kb were observed from 14 days postinjection
in PA and from 7 days postinjection in lung tissue. 18S, 18S rRNA.
B: densitometric analysis of 7.3-kb TN
isoform from autoradiograms shown in A
normalized to 28S rRNA loading controls showed that steady-state TN
mRNA levels increase with progressive pulmonary vascular disease.
[Reproduced with permission from Jones and Rabinovitch
(13).]
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Fig. 6.
Effect of exogenous TN-C (15 g/ml) on PASMC attachment
(A) and growth factor-dependent
proliferation (B). No significant
differences in attachment efficiency were noted between cells plated on
type I collagen alone or on TN-C-supplemented gels
(A). Similarly, SMC growth in
serum-free medium (SFM) was unaffected by addition (+) of exogenous
TN-C. In contrast, addition of bFGF or EGF to TN-C-treated cultures
resulted in a significant increase in cell number. Values are means ± SE. * P < 0.05 vs.
corresponding SFM level. P < 0.05 for difference related to TN-C.
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Fig. 7.
Hypothetical model for regulation and function of TN-C in vascular
SMCs. A: vascular SMCs attach and
spread on native type I collagen using
1-integrins. Under serum-free
conditions, cells withdraw from cell cycle and become quiescent. EGF-R,
EGF receptor. B: degradation of native
type I collagen by matrix metalloproteinases (MMPs) leads to exposure
of cryptic RGD sites that preferentially bind
3-subunit-containing integrins.
In turn, occupancy and activation of
3-integrins signal production
of TN-C. C: incorporation of
multivalent TN-C protein into underlying substrate leads to further
aggregation and activation of
3-containing integrins
(av 3)
and to accumulation of tyrosine-phosphorylated (Tyr-P) signaling
molecules and actin into a focal adhesion complex (FAC). Note that even
in absence of EGF ligand, TN-C-dependent reorganization of cytoskeleton
leads to clustering of actin-associated EGF-Rs.
D: addition of EGF ligand to clustered
EGF-Rs results in rapid and substantial tyrosine phosphorylation of
EGF-R and activation of downstream pathways, culminating in generation
of nuclear signals leading to cell proliferation. (Reproduced from P. L. Jones, J. Crack, and M. Rabinovitch. Journal of
Cell Biology 139: 279-293, 1997, by copyright
permission of the Rockefeller University Press.)
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FN AND THE VASCULAR SMC MIGRATORY RESPONSE |
To study how elastase may be related to SMC migration, we investigated
the mechanism whereby fetal ductus arteriosus SMCs migrate during the
formation of intimal cushions in late gestation. These structures
partially occlude the ductus lumen and ensure that it completely closes
in the postnatal period. We (33) had made the observation that the
ductus, rather than degrading elastin, assembles elastin poorly. The
by-products, namely the elastin peptides, convert the SMCs from
contractile to migratory by upregulating their production of FN (7, 9).
Ductus cells produce twofold more FN than aortic cells and appear quite
different in collagen gels (1-3). They have an elongated
"svelte" cometlike migratory phenotype compared with aortic
cells, which appear more rotund and look like helicopters. By adding FN
antibodies, the ductus cells revert to the contractile phenotype and
lose their jetlike profile and property (Fig.
8). Conversely, when aortic
SMCs are supplied with elastin peptides in the form of
-elastin or
when they are induced to assemble elastin poorly and to produce elastin peptides through the addition of chondroitin sulfate (8), we (7, 9)
have shown that they too upregulate their production of FN.

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Fig. 8.
Ductus arteriosus (DA) and aortic SMCs on collagen (2 mg/ml) gels.
A: DA SMCs 2 days after being seeded
onto surface of collagen gels. Cells exhibit a spindlelike elongated
morphology, and majority of cells are visible on surface of gels.
B: cell that has just migrated into
gel. By focusing into gel at a depth of 250 µm, this cell comes
clearly into focus. C: aortic cells 2 days after being seeded onto surface of gel exhibit a flattened,
stellate morphology. In presence of antibodies against fibronectin
(1:100), DA smooth muscle cells (D)
also display a more flattened, stellate appearance. [Reprinted
with permission from Boudreau et al. (3).]
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The regulation of FN is posttranscriptional because there is no
increase in FN mRNA levels as shown by Northern blot analysis (1). The
mechanism is related to the more efficient translation of FN mRNA in
the ductus SMCs compared with that in the aortic SMCs. This is related
to the increased production of a microtubule-associated protein, LC3,
that binds to a sequence in the 3'-untranslated region of FN mRNA
rich in A+U bases (adenosine-uridine-rich element). We can
increase the efficiency of translation of FN mRNA in aortic SMCs to
produce levels of FN comparable to those in ductus cells by
transfecting the aortic cells with LC3. Moreover, by sequestering LC3,
we (32) have been able to switch the ductus phenotype to nonmigratory
and prevent the increased production of FN that is associated with the
migratory phenotype. A more recent study from our laboratory (16) has
indicated that the production of LC3 may be a function of the redox
state and intracellular concentration of nitric oxide.
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APPLICATION TO SYSTEMIC ARTERY DISEASE |
The mechanisms elucidated by the above studies will, we hope, lead to
new therapeutic targets to prevent the progression of pulmonary
vascular disease and potentially even to induce its regression. The
windfall of our efforts has come through the extrapolation of our
findings to coronary artery disease. This new direction of our
laboratory was motivated by the loss of one of the pediatric heart
transplant patients to an accelerated form of atherosclerosis. Using
experimental models, we showed that elastase activity is high in
coronary arteries after transplant and that this activity could be
inhibited by exogenous elafin (23). The mechanism of graft coronary
artery disease involved the infiltration of inflammatory cells and the
consequent release of elastases and cytokines that interacted to induce
SMC proliferation and FN-dependent migration (4, 5, 18-20). To
test the effect of elastase in the pathophysiology of
posttransplant-accelerated coronary arteriopathy, the elastase inhibitor elafin was given by continuous intravenous administration to
rabbits after heterotopic heart transplantation. Elafin markedly reduced the number and severity of coronary artery intimal lesions (6)
(Fig. 9). A dividend in these studies is
that elafin also reduced the myocardial necrosis associated with
transplant rejection, presumably by inhibiting T-cell elastase.

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Fig. 9.
Representative photomicrographs of Movat pentachrome staining of
coronary arteries in host control and elafin-treated donor groups.
Normal-appearing host vessel (A)
contrasts with affected donor vessel
(B), showing a concentric intimal
lesion in control group, but a more normal-appearing artery is seen in
elafin-treated donor group (C).
Original magnification, ×200. (Reproduced from B. Cowan, O. Baron, J. Crack, C. Coulber, G. J. Wilson, and M. Rabinovitch.
The Journal of Clinical Investigation
97: 2452-2468, 1996, by copyright permission of The American
Society for Clinical Investigation.)
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ACKNOWLEDGEMENTS |
M. Rabinovitch is a Heart and Stroke Foundation of Ontario Research
Endowed Chair.
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FOOTNOTES |
1
Reference 27 as well as Refs. 6, 11-13,
16, and 32 were published after the Julius Comroe Lecture was given at
the Experimental Biology meeting in 1996.
This lecture was part of the Distinguished Lectureship Series
given at the Experimental Biology meeting in 1996 in Washington, DC.
Address for reprint requests and other correspondence: M. Rabinovitch,
Division of Cardiovascular Research, Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada M5G 1X8 (E-mail:
mr{at}sickkids.on.ca).
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