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J. Biol. Chem., Vol. 277, Issue 43, 40499-40504, October 25, 2002
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,,
,¶**
From the Department of Clinical Biochemistry and the
§ School of Pharmacy, Hadassah University Hospital and
Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel, the ¶ Departments of Pathology and Laboratory Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 19104, and
Attenuon, L. L. C., San Diego, California 92121
Received for publication, July 17, 2002
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Urokinase plasminogen activator (uPA)
is a multifunctional protein that has been implicated in several
physiological and pathological processes involving cell adhesion and
migration in addition to fibrinolysis. In a previous study we found
that two-chain urokinase plasminogen activator (tcuPA) stimulates
phenylephrine-induced vasoconstriction of isolated rat aortic
rings. In the present paper we report that uPA Urokinase plasminogen activator
(uPA)1 is a multifunctional
protein that has been implicated in several physiological and
pathological processes, including fibrinolysis. Transgenic mice with a
targeted disruption in the uPA gene (uPA uPA has also been implicated in other pathophysiological processes,
such as pulmonary inflammation and repair, in which the relationship to
fibrinolysis is less clear. For example, uPA In a previous study we found that uPA enhances phenylephrine and
endothelin-induced vasoconstriction of aortic rings isolated from rats
(9). The possibility that uPA contributes to the regulation of vascular
tone may help to explain some of the phenotypic changes described in
uPA These experiments, having been performed using rat aortic rings and
human uPA, also raised a question as to the nature of the vascular
receptor that mediates the contractile properties of uPA (9). Because
rat uPAR does not bind human uPA (10), the results suggest that uPAR is
not directly responsible for the observed vasoactivity, but they leave
the identity of this other "uPA receptor" unresolved. Also
uncertain is the effect of PAI-1, which binds to tcuPA with high
affinity and neutralizes its proteolytic activity (11). The results of
several studies indicate that PAI-1 is elevated in the plasma of
patients with hypertension, and reduction of blood pressure by certain
classes of anti-hypertensive agents is associated with a decrease in
PAI-1 concentration (12-15). Whether this is a cause or result of
therapy is unclear.
To address these questions, we turned to uPA Materials--
Recombinant full-length uPA and a uPA
variant lacking the kringle were prepared in S2 cells and purified as
in Ref. 9. Phenylephrine (PE) was purchased from Sigma.
uPA Blood Pressure Recording--
Mean arterial blood pressure
(MABP) was measured as in Ref. 9. Mice were anesthetized by
intraperitoneal administration of 10 mg/Kg
In some experiments, tcuPA, ATF, tcuPA/PAI-1, or tcuPA/EEIIMD complex
were infused through the cannula placed in the right jugular using a
multisyringe pump at a rate of 5 µl/min (maximum 60 min), and the
MABP was determined beginning 10 min later. In other experiments,
anti-LRP antibody or control IgG was administered by constant infusion
for 5 min followed by co-infusion of antibody with tcuPA or ATF for the
remainder of the experiment.
Contractile Response--
Experiments were performed as
described in Ref. 9. Mice were sacrificed by exsanguination. Thoracic
aortae were removed with care to avoid damage to the endothelium,
dissected free of fat and connective tissue, and cut into transverse
rings 5 mm in length (17-20). In another set of experiments, the rings
were gently rotated on a stainless steel rod to remove the endothelium (denuded aorta). To record isometric tension the rings were mounted in
a 10-ml bath containing oxygenated (95% O2, 5%
CO2) solution of Krebs-Henseleit (KH) buffer (144 mM NaCl, 5.9 mM KCl, 1.6 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2PO4, 25 mM
NaHCO3, and 11.1 mM D-glucose).
Each aortic ring was then contracted by adding PE in stepwise
increments from 10
The half-maximal effective concentration (EC50) was
calculated from data that show the response of the aortic rings to
increasing concentration of PE and includes the data from at least
three repetitions of the same experiment. After drawing a figure
portraying the outcome, two lines that intersect with the y
and x axes were drawn to determine the PE concentration that
induces 50% of the maximal effect.
Half-life of uPA--
The life-time of uPA in the
circulation was determined as described previously (5). Briefly, mice
were injected intravenously with a single dose of
125I-labeled tcuPA or 125I-labeled We previously reported that tcuPA, its ATF, and kringle domain
enhance PE-induced vasoconstriction of rat aortic rings (9). In the
present paper, we examined the contribution of endogenous uPA to blood
pressure regulation in mice. To do so, we first compared the MABP of
uPA
/
mice have a significantly lower mean arterial blood pressure than do
wild type mice and that aortic rings from uPA/ mice
show an attenuated contractile response to phenylephrine. In contrast,
the blood pressure of urokinase receptor knockout (uPAR/) mice and the response of their isolated aortic
rings to phenylephrine were normal, indicating that the effect of uPA
on vascular contraction is independent of uPAR. Addition of mouse and
human uPA almost completely reversed both the impaired vascular
contractility and the lower arterial blood pressure in
vivo. The in vitro and in vivo effects of
infused uPA on aortic contractility and the restoration of normal blood
pressure in uPA/ mice were prevented by antibody to
low-density lipoprotein receptor-related protein/
2-macroglobulin receptor (LRP). A modified form
of uPA that lacks the kringle failed to restore the blood pressure in uPA/ mice, notwithstanding having a longer half-life in
the circulation. Ligands that regulate the interaction of uPA with LRP,
such as PAI-1 or the PAI-1-derived peptide (EEIIMD), abolished the
vasoactivity of tcuPA in vitro and in vivo.
These studies identify a novel signal transducing cellular receptor
pathway involved in the regulation of vascular contractility.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/) are prone to
form thrombi when exposed to endotoxin (1) or hypoxia (2, 3) or when
the uPA gene is disrupted in otherwise healthy tPA/
mice (1, 4). We recently reported that clearance of pulmonary microemboli in uPA/ mice is delayed, despite the
presence of an intact tPA system (5).
/ mice are
more susceptible to lethal pulmonary infection (6) and to the
development of pulmonary fibrosis (7), end-points that might reflect
contribution of uPA in cell adhesion (8) and migration to these
phenotypes. However, the mechanism by which uPA is involved in these
processes has not been established.
/ mice and perhaps provide a broader understanding
of the role played by uPA in certain physiological and pathological
processes, such as inflammation (6) and metastasis. It was, therefore, of interest to examine the contribution of endogenous uPA to the regulation of vasoactivity in vivo.
/ mice. In
the present paper we report that uPA/ mice have lower
blood pressure than wild type (WT) animals and that the contractility
of their blood vessels is attenuated in vitro and in
vivo. We also report that the stimulatory effect of tcuPA on
vascular smooth muscle cell activation is mediated by LRP and through a
process that inhibited by PAI-1 but independent of its proteolytic activity.
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/ and uPAR/ mice on a C57/black
background and wild type C57/black mice were purchased from Jackson
Laboratories. Four-month-old male mice were used in all studies.
Recombinant 39-kDa receptor-associated protein (rRAP) and purified
soluble LRP were generously provided by Dr. D. Strickland (American Red
Cross, Rockville, MD). Anti-LRP antibodies were also provided by D. Strickland and by American Diagnostica Inc. (Greenwich, CT). The
peptides (EEIIMD and REIIMD) were synthesized as previously described
(16). tcuPA and its amino-terminal fragment (ATF) were prepared and
purified as in Ref. 9.
1 ketamine and
50 mg/Kg xylazine. One cannula was placed in the left carotid artery to
record the mean arterial blood pressure, and a second through which PE
(0.3 µg per animal) was administered was placed in the right jugular
vein. Blood pressure was monitored continuously through a transducer
placed in the left carotid cannula using the CARDIOSYS computerized
system (ExperimentiaÆ, Budapest, Hungary).
10 M to 105
M. In other experiments, uPA was added 15 min before
addition of PE. In each experiment, rings exposed to KH buffer alone
were analyzed in parallel. Isometric tension was measured with a force displacement transducer and recorded online using a computerized system
(ExperimentiaÆ). The half-maximal effective concentration (EC50) was calculated by measuring the response of the
aortic rings to increasing concentration of PE. In all studies, results are shown as the mean ± S.E. from three experiments.
k-tcuPA
(0.1 mg/kg). Blood was withdrawn by intracardiac injection at the
indicated time points and counted for radioactivity.
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/ mice with that of WT controls. The data presented
in Table I show that the blood pressure
of uPA/ mice was significantly lower than that of WT
animals. The MABP in WT mice was 73.17 ± 3.97 mm Hg
(n = 6), whereas the uPA/ mice had an
MABP of 53.83 ± 3.54 mm Hg (n = 6;
p = 0.0005 in the paired t test). The lower
MABP in uPA/ mice reflected both a lowered systolic and
diastolic pressures. The systolic and diastolic pressures in the
uPA/ mice were 63.17 ± 2.88 and 44.51 ± 4.43 mm Hg, while those in the WT mice were 87.6 ± 3.93 and
58.81 ± 3.86 mm Hg, respectively.
Basal MABP of wild type and knock-out mice
/ mice by introducing a sensor through the carotid
artery, as described under "Materials and Methods."
Similar differences were observed when the contractions of isolated
aortic rings from the two sets of mice were compared. Aortic rings from
uPA/ mice had a reduced response to phenylephrine,
i.e. rings from WT mice had an EC50 of 7.94 nM PE, whereas uPA/ had an EC50
of 251 nM (Fig. 1).
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Although aortic rings from uPA/ mice showed
an impaired contractile response to PE, their maximal response did not
differ from that of WT animals at high concentrations of agonist (Fig.
1), indicating that these mice do not lack vascular receptors and that
the downstream intracellular signal transduction mechanisms are intact.
In support of this conclusion, injection of PE (0.3 µg) increased
MABP in the WT and uPA/ animals to the same level
(127 ± 3 mm Hg in the WT compared with 128 ± 4 mm Hg in
uPA/ mice). Moreover, the impaired contractility of
aortic rings from uPA/ mice was almost completely
reversed by the addition of 1 nM mouse or human tcuPA (Fig.
2). These results indicate that it is the deficiency of uPA itself and not a secondary defect in the vasculature of these mice that underlies the difference in phenotype.
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Having observed that uPA is involved in the regulation of the
vasoactivity in vivo, our next goal was to identify the
responsible cellular receptor. The finding that human and mouse uPA had
a similar effect on the tension in mouse aortic rings (Fig. 2) suggests strongly that uPAR is not directly involved in the uPA-mediated vasocontractility. However, to examine the involvement of uPAR directly, we measured mean aortic blood pressure in
uPAR/ mice. The MABP of uPAR/ mice
(71 ± 4.29 mm Hg, n = 6) and WT mice were
virtually identical. Second, the response of isolated aortic rings from
uPAR/ mice to PE was similar to that of WT mice, with
an EC50 of 8.45 nM.
It is known that tcuPA binds to LRP (21, 22) and that binding of
ligands, such as 2-macroglobulin, to LRP triggers
mobilization of Ca2+ in certain cell types (23). Therefore,
we evaluated LRP as a candidate receptor involved in uPA-mediated vasoconstriction.
To examine the potential involvement of LRP in the tcuPA-induced
vasoactivity, we used two different approaches. First, we studied the
effect of the receptor-associated protein (RAP) on tcuPA-mediated
contractility. RAP is a 39-kDa protein that co-purifies with LRP and
inhibits the binding of tcuPA (24). rRAP (20 nM) prevented
uPA from restoring normal contractility to aortic rings from
uPA/ mice. Second, anti-LRP antibodies prevented (20 nM) tcuPA-enhanced contraction, whereas a blocking antibody
to the LDL receptor had no effect (Fig.
3). Neither rRAP nor anti-LRP affected
PE-induced vasoconstriction in the absence of uPA (Fig. 3).
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LRP has been shown to mediate the clearance of uPA from the
circulation in vivo, i.e. blocking LRP by RAP
increases the half-life of uPA (25). Therefore, we next examined the
effect of anti-LRP antibodies on the regulation of blood pressure by
uPA in vivo. Injecting human uPA to uPA/
mice (0.1 mg/kg) restored the MABP to normal (Fig.
4A); higher doses of uPA had
no additional effect (not shown). Preinjection of anti-LRP abolished
the restoration of blood pressure by uPA (Fig. 4A) and
increased its half-life in the circulation (Fig. 4B).
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We previously reported (9) that the stimulatory effect of uPA on
PE-induced vasoconstriction is mediated by its kringle. In agreement
with this, a uPA variant in which the kringle was deleted (k-uPA)
was unable to restore blood pressure in uPA/ mice (Fig.
4A). Moreover, the half-life of k-uPA was prolonged comparably to that of WT uPA measured in the presence of anti-LRP (Fig.
4B).
Plasminogen activator inhibitor type 1 (PAI-1) binds tightly to tcuPA
and enhances the affinity of the resultant complexes for LRP (26, 27).
To examine the effect of PAI-1 on uPA-mediated contractility, aortic
rings were contracted by adding increasing concentrations of PE in the
presence of 1 nM tcuPA alone or together with equimolar
concentrations of PAI-1. As expected, tcuPA (1 nM)
augmented the PE-induced contraction of aortic rings from uPA/ mice, decreasing the EC50 of PE from
254 to 9.43 nM (Fig. 5). In
the presence of an equimolar concentration of PAI-1 the effect of tcuPA
was abolished (EC50 248 nM) (Fig.
6).
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tcuPA binds to PAI-1 through two distinct epitopes, one
involving its catalytic site. The other site, EEIIMD, comprises
residues 350-355 in PAI, which interacts with residues 179-184 in uPA
(28). We previously found that the isolated EEIIMD peptide inhibits the
binding of PAI-1 to tcuPA and regulates the binding of scuPA to
cell-associated and purified LRP (16). Therefore, we examined the effect of EEIIMD on the vasocontractile properties of tcuPA. EEIIMD
(1 µM) abolished the capacity of tcuPA to restore
PE-induced vasoconstriction of aortic rings from uPA/
mice to normal (Fig. 6). In contrast, the control peptide, REIIMD, which has almost no effect on PAI-1 binding to uPA (16), did not affect
tcuPA-mediated vasoactivity. Neither did PAI-1 nor EEIIMD alone alter
the contraction of aortic rings. The inhibitory effect of PAI-1 and the
PAI-1-derived peptide on tcuPA vasoactivity was also seen using aortic
rings from WT mice (not shown). The vasoactive effect of the uPA ATF is
similar to that of tcuPA (9), but ATF lacks proteolytic activity and
the binding epitopes for PAI-1 and EEIIMD peptide. PAI-1 had no effect
on ATF-induced vasoactivity (Fig. 7). The
same result was obtained with 1 µM EEIIMD (not shown), excluding an effect of PAI-1 or EEIIMD on other components of the
system.
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PAI-1 also modulated the procontractile effect of tcuPA in
vivo. tcuPA (0.1 mg/kg) no longer was able to restore the blood pressure of uPA/ mice in the presence of an equimolar
concentration (~40 nM) of PAI-1 (Fig.
8); the same outcome was observed after
infusion of EEIIMD. In contrast, ATF (0.1 mg/kg), which had the same
procontractile effect as full-length tcuPA, was refractory to PAI-1 and
to EEIIMD (Fig. 8).
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To examine the role of the endothelium and specifically that of eNO
synthase in uPA-mediated vasoconstriction, we first studied the effect
of tcuPA on denuded rat aortic rings. We used rat aortic rings because
it is technically difficult to denude aortic rings from mice
completely and atraumatically. As previously reported by us (9), tcuPA
stimulated the PE-induced constriction of isolated rat aortic rings but
had no vasoactive effect on denuded rings (Fig.
9). Second, L-NAME inhibited uPA-mediated
contraction of rat (Fig. 9) and mouse (not shown) aortic rings.
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DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our data show that uPA participates in the endogenous regulation
of blood pressure in vivo. This conclusion is based on the following observations. First, uPA/ mice have reduced
systolic and diastolic arterial blood pressures. Second, aortic rings
isolated from uPA/ mice have impaired contractile
responses to low doses of phenylephrine. Third, the lower blood
pressure in uPA/ mice and the attenuated response of
isolated aortic rings from these mice are restored to normal by
addition of uPA exogenously. Fourth, ligands that bind to uPA, such as
PAI-1 or the PAI-1-derived peptide, neutralize its vasoactivity.
The observations that aortic rings from uPAR/ mice
respond normally to PE and that these mice have a normal blood pressure indicates that the effect of uPA is independent of this receptor. The
difference in blood pressure observed in uPA/ and
uPAR/ mice is reminiscent of other differences in their
phenotypes (4) and supports the existence of additional uPA receptors.
The finding that anti-LRP antibodies and rRAP abolish the effect of uPA in vitro and in vivo suggests that the effect of uPA on vascular contractility is mediated through LRP. This conclusion is supported by the observation that ligands that affect the interaction of tcuPA with LRP (PAI-1 and EEIIMD) attenuate the vasoactive effect of uPA. Our findings support the hypothesis of Bacskai et al. (23) that LRP can act as a signal-transducing receptor to mobilize release of intracellular Ca2+, which is necessary for contraction of vascular smooth muscle cells.
The ability of PAI-1 to neutralize the provasocontractile effects of uPA is relevant to understanding the behavior of LRP as well as smooth muscle cell contraction. PAI-1 binds to LRP (26, 27), but does not affect PE-induced vasoconstriction unless complexed with tcuPA. Indeed, PAI-1 and its derived peptide (EEIIMD) inhibit the vasocontractile effect of uPA although both augment binding of urokinase to LRP (16, 26, 27). These findings indicate that not all LRP ligands transduce signals leading to vasoconstriction. Additional study is needed to understand how LRP differentially handles the diverse ligands that it encounters. Several groups have reported that PAI-1 levels are elevated in hypertensive patients and that reduction of blood pressure by certain, but not all, forms of medical treatment are associated with a decrease in PAI-1 (12-15). Whether changes in PAI-1 are a cause or consequence of changes in vascular tone is unknown. Nevertheless, our studies raise the possibility that vascular tone and other critical behaviors of vascular smooth muscle cells are regulated in part through LRP and can be modified by PAI-1-derived peptides.
The mechanism by which uPA internalized by LRP signals intracellularly requires additional study. It is widely accepted that LRP is an endocytic receptor that delivers ligands to lysosomes. Recently, LRP has also been shown to initiate intracellular signaling. The human immunodeficiency virus-Tat protein binds to LRP and is internalized into endosomes and later translocated to the nucleus, by a process that is poorly understood, where it stimulates transcription (29). Furthermore, Pseudomonas exotoxin A, which mediates ADP-ribosylation of elongation factor 2 in the cytoplasm, enters the cell exclusively via LRP (30). The toxin is composed of a single-chain polypeptide that harbors a fusogenic domain that mediates its translocation into the cytoplasm (30). It is possible that a fraction of the unbound uPA may escape proteolysis and exit the lysosomes to reach another location where it can initiate signal transduction. Conversely, binding of uPA to PAI-1 may change its destination by accelerating its degradation, thereby impeding signal transduction. This hypothesis is in accord with our previous data that show that PAI-1 and PAI-1-derived peptide (EEIIMD) increases the degradation of uPA (16, 31).
It is noteworthy that the differences we found in blood pressure of
anesthetized WT (and uPAR/) compared with
uPA/ mice were recorded in the absence of any exogenous
vasoactive compounds. Injection of PE increased the MABP in WT and
uPA/ mice to the same level, and a similar effect was
seen in isolated aortic rings. These findings suggest that under
certain physiological and/or pathological conditions, such as pain or
stress, the decreased blood pressure in uPA/ may not be
evident. This is consistent with the absence of an effect of uPA on
aortic blood pressure measured through an open abdominal incision in a
setting associated with significant hypotension (32).
Although we have shown that urokinase acts on LRP as a ligand to
modulate blood vessel reactivity, the details of the downstream signaling pathway and the involvement for eNOS will also require additional study. Better insights into this process may provide information that will help to elucidate the relationship among the
fibrinolytic and inflammatory systems, vasoactivity, and cancer invasiveness, in which urokinase and PAI-1 are known to play key roles
(33). Furthermore, a better understanding of the mechanism by which uPA
regulated vasoactivity may facilitate the design of thrombolytic agents
with more selective fibrinolytic activity or antagonists that block
vascular effects that contribute to untoward inflammatory reactions or
tumor cell migration.
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FOOTNOTES |
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* This work was supported, in part, by National Institutes of Health Grants HL67381, HL60169, R03 TW01468, and HL58107 and a grant from American Diagnostica, Inc.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Pennsylvania, 513A Stellar-Chance, 422 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-662-3966; Fax: 215-573-2012; E-mail: higazi@mail.med.upenn.edu.
Published, JBC Papers in Press, August 8, 2002, DOI 10.1074/jbc.M207172200
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ABBREVIATIONS |
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The abbreviations used are:
uPA, urokinase
plasminogen activator;
tcuPA, two-chain urokinase plasminogen
activator;
WT, wild type;
LRP, low-density lipoprotein receptor-related
protein/2-macroglobulin receptor;
PE, phenylephrine;
RAP, receptor-associated protein;
rRAP, recombinant RAP;
ATF, amino-terminal fragment;
MABP, mean arterial blood pressure;
PAI, plasminogen activator inhibitor;
uPAR, urokinase receptor.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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