From the Department of Pathology, University of Washington (Seattle).
Correspondence to E.J. Su, Department of Pathology, Box 357335, Seattle WA 98195. E-mail enmingsu{at}u.washington.edu
The purpose of this study was to investigate the relationship
between the mitogenic and hypertensive effects of Ang II.
With cotreatment by hydralazine, the hypertensive effect of Ang
II can be neutralized, thus allowing us to study the proliferative
effect of Ang II without the interference of blood pressure. We found
that Ang II stimulated SMC replication in the mesenteric arteries
within 1 week of treatment and that this proliferative effect was not
abolished by hydralazine treatment. This result demonstrates
that the mitogenic activities of Ang II are not dependent
on its pressor effect. Our results provide direct evidence for the
first time that Ang II stimulates SMC replication in the mesenteric
microvessels even without the elevation of blood pressure.
One week after pump implantation, animals were
anesthetized as described above and euthanized with an
intravenous injection of pentobarbital. Two rings of the
carotid artery were taken from each animal and immersion fixed in
either 4% paraformaldehyde or methyl Carnoy's
fixative. Rings were routinely processed and paraffin embedded. The
mesenteric bed including the gut was cut into 2 pieces. One was
immersed in 4% paraformaldehyde and the other in
methyl Carnoy's fixative.
Mesenteric Artery Dissection and Preparation
Histochemistry and Morphometry
Systolic Blood Pressures
Measurement of Vascular Cross-sectional Area
Statistics
Effect of Ang II on Cross-sectional Area of the Arterial
Wall
Ang II increased cross-sectional area in the tunica media of the
type III microvessels (50% increase compared with Ringer's animals;
Figure 3
We previously reported that Ang II treatment increased the size
of the type I microvessel approximately 2-fold to
5-fold.5 As with type III microvessels, this
increase was not abolished by cotreatment with Ang II and
hydralazine (Figure 4
Effect of Ang II and Antihypertensive Treatment on DNA Replication
in the Carotid Artery and Microvessels
In type III microvessels, Ang II stimulated medial SMC
replication. The increase in replication rate was 26-fold compared with
the control, Ringer's infused animals. Cotreatment with Ang II and
hydralazine, although blunting the increase in blood pressure,
did not diminish the increase in DNA replication. Ang II plus
hydralazine treatment produced an
Similarly, Ang II treatment induced an extraordinarily high
replication rate in the type I vessels of the mesentery. Using the BrdU
immunostaining technique, we were able to stain the
proliferating SMCs, and these results are summarized in Figure 8
The existing evidence for mitogenic effects of Ang
II, primarily based on in vitro studies, is confusing. Geisterfer et
al8 used rat aortic SMCs to evaluate the role of
Ang II in regulating SMC growth. They found that Ang II failed to
stimulate SMCs to replicate either in serum-free conditions or with
10% fetal bovine serum. However, Ang II was able to increase protein
synthesis in these cells. On the other hand, Campbell and
Robertson14 reported elevated DNA synthesis in
human SMCs due to Ang II treatment. The differences between these two
studies may originate from the sources of SMCs that they used in these
experiments. We and others have shown that rat SMCs are diverse,
including markedly different growth factor requirements that depend on
the donor's original age and the manner in which the cells were placed
in culture.
Gibbons et al15 offered a different
hypothesis to explain the effects of Ang II in
vitro.15 They demonstrated that Ang II induced
both hypertrophy and hyperplasia in the same rat SMC line
through a mechanism suggested to be modulated by TGF-ß1 because
cotreatment with neutralizing anti–TGF-ß1 and Ang II increased DNA
synthesis in SMCs. On the contrary, Stouffer and
Owens16 reported the opposite
findings.16 When using anti–TGF-ß1 antibody,
they detected decreased DNA synthesis in rat aortic SMCs treated with
Ang II. The differences may be ascribed to differences in the strains
of rats used in the two experiments because Gibbons et al used SMCs
derived from Sprague-Dawley rats, whereas Stouffer and Owens obtained
SMCs from spontaneously hypertensive rats. It is conceivable that SMCs
from different rat strains may exhibit differential responses to growth
stimuli, such as Ang II or TGF-ß1.
The proliferative effect of Ang II may also depend on bFGF. We
have shown that in vivo at least part of the proliferative effect of
Ang II is due to bFGF.17 Using antisense
oligomers complimentary to bFGF, Itoh et al18
were able to inhibit Ang II–induced DNA synthesis in SMCs in
vitro.18 Therefore, the growth-stimulating
effects of Ang II may involve TGF-ß1 and bFGF and also depend on the
source of the SMCs.
The mitogenic effect of Ang II in vivo is even more
difficult to evaluate. In vivo studies have shown that Ang II is able
to stimulate SMC DNA replication in large and small
arteries.5 6 The etiology of this
mitogenic effect is difficult to assess, however, given the
concomitant development of hypertension in the treated animals.
Moreover, Ang II has been shown to augment SMC DNA replication in the
neointima, even months after balloon
injury.7 Evidence for a local effect of Ang II
rather than an indirect effect of blood pressure comes from
antagonist studies in nonhypertensive models. Studies with
an angiotensin type 1 receptor antagonist have
shown that Ang II is important in the replicative response after
balloon injury.19 There is also evidence that
other mediators may be involved in Ang II–stimulated SMC replication.
Our laboratory previously reported that anti-bFGF antibody blocked the
proliferative effect of Ang II in carotid arteries and type II and III
mesenteric microvessels.17 Therefore, the
mitogenic effect of Ang II may be dependent on the presence
of bFGF. Ang II may also mediate its effect in part via the ß1
adrenergic receptor, since blocking this receptor can attenuate the
proliferative response to Ang II13 while
stimulating this receptor can promote SMC
growth.20 These pathways may all act together to
elicit the mitogenic effects of Ang II in vivo.
Other data also suggest a direct effect of Ang II on the vessel
wall. For example, Griffin et al12 found an
increase in cross-sectional area after 1 week of Ang II treatment,
independent of blood pressure.12 However, they
did not determine whether this increase was due to proliferation of
SMCs. We found that Ang II was a mitogen for vascular SMCs in a variety
of vessels, including the carotid artery and type I and III
microvessels in this study. The dramatic increase in SMC replication
observed after 1 week of Ang II infusion was blood pressure
independent. We also found that Ang II caused significant structural
changes in the type III microvessels, ie, an increase in
cross-sectional area independent of blood pressure, which confirmed the
findings of Griffin et al. This suggests that the mitogenic
effect of Ang II may be responsible for the change in mass. Since
changes in resistance vessel mass have profound effects on the
responsiveness of blood pressure to
vasoconstrictors,4 this proliferative event could
be important to the establishment of a maintained hypertensive state if
it results in hyperplasia as well as hypertrophy.
Our data combined with those of Griffin et al raise the important
issue of whether the remodeling of vessel walls to increase their
resistance to vasoactive agents in hypertension may depend in part on
the number of cells in the walls. The idea that hyperplasia is
important is of interest because DNA does not turn over in vessel walls
under normal conditions. If cell replication is important, then two
kinds of drug effects may be relevant to antihypertensive therapy.
First, we may want to consider drugs that block cell replication. These
may or may not be the same drugs that induce the other effects of
antihypertensive medications. Thus, the present study suggests that
hydralazine may not be as effective as
angiotensin-converting enzyme inhibitors in
treating blood pressure. Second, we may be interested in drugs that
modulate cell number. In this regard, deBlois et
al21 reported that calcium channel blockers were
able to induce apoptosis and reduce cell numbers by 40% in the
aorta of spontaneously hypertensive rats.
The results of this investigation help to separate the
hypertensive effects of Ang II from its mitogenic effects.
These findings strongly suggest that Ang II behaves as a mitogen in
vivo, although the precise mechanism is not clear. Nonetheless, our
results have important implications for understanding the mechanism for
vascular hypertrophy in hypertensive patients.
Received December 10, 1997;
first decision January 8, 1998;
accepted January 30, 1998.
2.
Mulvany MJ. Peripheral vasculature in
essential hypertension. Clin Exp Pharmacol Physiol. 1996;23:S6–S10.[Medline]
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3.
Schwartz SM, Ross R. Cellular proliferation in
atherosclerosis and hypertension. Prog Cardiovasc
Dis. 1984;26:355–372.[Medline]
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4.
Folkow B. Physiological aspects of
primary hypertension. Physiol Rev. 1982;62:347–504.
5.
Wiener J, Lombardi DM, Su EJ, Schwartz SM.
Immunohistochemical and molecular characterization of the differential
response of the rat mesenteric microvasculature to
angiotensin II infusion. J Vasc Res. 1996;33:195–208.[Medline]
[Order article via Infotrieve]
6.
deBlois D, Lombardi DM, Su EJ, Clowes AW, Schwartz SM,
Giachelli CM. Angiotensin II induction of osteopontin
expression and DNA replication in rat arteries.
Hypertension. 1996;28:1055–1063.
7.
Daemen MJAP, Lombardi DM, Bosman FT, Schwartz SM.
Angiotensin II induces smooth muscle cell proliferation in
the normal and injured arterial wall. Circ Res. 1991;68:450–456.
8.
Geisterfer AA, Peach MJ, Owens GK.
Angiotensin II induces hypertrophy, not
hyperplasia, of cultured rat aortic smooth muscle cells. Circ
Res. 1988;62:749–756.
9.
Berk BC, Vekshtein V, Gordon HM, Tsuda T.
Angiotensin II–stimulated protein synthesis in cultured
vascular smooth muscle cells. Hypertension. 1989;13:305–314.
10.
Bunkenburg B, van Amelsvoort T, Rogg H, Wood JM.
Receptor-mediated effects of angiotensin II on growth of
vascular smooth muscle cells from spontaneously hypertensive rats.
Hypertension. 1992;20:746–754.
11.
Paquet JL, Baudouin LM, Brunelle G, Meyer P.
Angiotensin II-induced proliferation of aortic myocytes in
spontaneously hypertensive rats. J Hypertens. 1990;8:565–572.[Medline]
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12.
Griffin S, Brown W, MacPherson F, McGrath J, Wilson V,
Korsgaard N, Mulvany M, Lever A. Angiotensin II causes
vascular hypertrophy in part by a nonpressor mechanism.
Hypertension. 1991;17:626–635.
13.
Van Kleef EM, Smits JFM, DeMey JGR, Cleutjens JPM,
Lombardi DM, Schwartz SM, Daemen MJAP.
14.
Campbell BM, Robertson ALJ. Effects of
angiotensin II and vasopressin on human smooth muscle cells
in vitro. Exp Mol Pathol. 1981;35:265–276.[Medline]
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15.
Gibbons G, Pratt R, Dzau V. Vascular smooth muscle cell
hypertrophy vs hyperplasia: autocrine TGF-ß-1
expression determines growth response to angiotensin II.
J Clin Invest. 1992;90:456–461.
16.
Stouffer GA, Owens GK. Angiotensin
II–induced mitogenesis of spontaneously hypertensive rat–derived
cultured SMC is dependent on autocrine production of
TGF-ß. Circ Res. 1992;70:820–828.
17.
Su EJ, Lombardi DM, Wiener J, Daemen MJAP, Reidy MA,
Schwartz SM. Mitogenic effect of angiotensin II
on rat carotid arteries and type II or III mesenteric microvessels, but
not type I mesenteric microvessels, is mediated by
endogenous basic fibroblast growth factor. Circ
Res. 1998;82:321–327.
18.
Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ.
Multiple autocrine growth factors modulate vascular smooth muscle cell
growth response to angiotensin II. J Clin
Invest. 1993;91:2268–2274.
19.
Prescott M, Webb R, Reidy MA. ACE
inhibitors vs AII, AT1 receptor antagonist:
effects on smooth muscle cell migration and proliferation after balloon
catheter injury. Am J Pathol. 1991;139:1291–1302.[Abstract]
20.
deBlois D, Schwartz SM, Van Kleef EM, Su EJ, Griffin
KA, Bidani AK, Daemen MJAP, Lombardi DM. Chronic
21.
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© 1998 American Heart Association, Inc.
Scientific Contributions
Angiotensin II Induces Vascular Smooth Muscle Cell Replication Independent of Blood Pressure
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—The purpose of this
investigation was to evaluate the role of blood pressure in the
proliferative response of vascular smooth muscle cells to systemic
infusion of angiotensin II (Ang II). Our laboratory has
previously shown that infusion of Ang II induces smooth muscle cell
proliferation in rat mesenteric vessels and carotid arteries. Ang II, a
strong vasopressor, raised systolic blood pressure in rats from
120 to 200 mm Hg at a dose of 435 ng ·
kg-1 · min-1 after 1 week of
treatment. The question arises as to whether this development of
hypertension is a primary contributor to the replicative activities
observed in the arterial wall of the mesenteric arteries or
the carotid arteries or whether Ang II alone, without an increase in
blood pressure, is sufficient to stimulate proliferation in these
vessels. In the previous studies, we found that Ang II stimulated
smooth muscle cell replication in the carotid artery and in type III
and type I mesenteric microvessels. This study demonstrates that
although administration of hydralazine normalizes the animals'
blood pressures, it does not suppress the mitogenic effect
of Ang II. Thus, it appears that Ang II has a direct effect on
cell proliferation.
Key Words: angiotensin II • hyperplasia • hypertrophy • muscle, smooth • mesenteric arteries • proliferation
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Structural
changes of resistance vessels play a major role in regulating blood
pressure.1 2 3 Because thickened walls of
resistance vessels may act as a vascular "amplifier" to raise blood
pressure,4 factors that regulate the growth of
SMCs may contribute to the development of hypertension by inducing
thickening of the resistance vessels. Ang II, a potent vasoconstrictor,
is able to stimulate SMC growth in the vascular wall when it is
administered in vivo.5 6 7 When Ang II is given in
vitro, it increases either the size8 9 or the
number10 11 of SMCs. When Ang II was given in
vivo, it caused vascular hypertrophy in resistance vessels
of the mesentery12 and induced multiple forms of
hyperproliferative responses in the mesenteric
vessels.5 These results were complicated by the
fact that Ang II also raised SBP. The key question is whether these
hyperproliferative responses are due to the hemodynamic
effect or to a direct action of Ang II.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Experimental Protocol
Three-month-old male Sprague-Dawley rats (
450 g; Zivic
Miller, Allison, Pa) were used for these studies. All animals were
allowed standard rat chow and water ad libitum. On day 0, animals were
anesthetized with ketamine HCl (50 mg/kg body wt),
xylazine (5 mg/kg body wt), and acepromazine (1 mg/kg body wt)
administered intramuscularly. Osmotic pumps (Alza Corp) were surgically
implanted subcutaneously in the backs of the rats. The animals were
randomly assigned to one of four groups. (1) Animals in the Ang
II–treated group received a pump (model 2001) filled with Ang II
(Sigma Chemical Co) and delivered at a dosage of 435 ng ·
kg-1 · min-1 in
Ringer's and a second pump (model 2001) filled with BrdU diluted with
Ringer's at 30 mg/mL. (2) Animals in the Ang II and
hydralazine treatment group received three pumps. In addition
to the Ang II and BrdU pumps, they also received a hydralazine
pump (model 2ML1, 26 mg · kg ·
-1d-1). (3) In animals
treated with Ringer's, a pump filled with Ringer's was implanted
along with a BrdU pump. (4) In animals treated with Ringer's plus
hydralazine, a hydralazine pump (model 2ML1, 26 mg
· kg-1 · d-1)
and a BrdU pump were implanted. Animals recovered from
anesthesia in 2 hours. Systolic blood pressure
was measured on days 0, 3, 4, 5, and 6 to demonstrate the elevation of
blood pressure due to Ang II infusion. The Animal Care Committee of the
University of Washington approved all procedures.
A random loop of small intestine was cut out and cleaned
while being viewed under a dissection microscope to retrieve
microvessel types I, II, and III as described elsewhere and in Figure 2
. A minimum of 3 type III and 8 to 10 type I vessels from each animal
were routinely processed, embedded in paraffin, and examined.
View larger version (21K):
[in a new window]
Figure 2. Classification of mesenteric arteries: type I,
type II, type III, and type IV mesenteric microvessels.
Five-micron-thick paraffin sections of carotid arteries
were cut. Three sections at least 50 µm apart were stained with
anti-BrdU by utilizing a specific monoclonal antibody (a kind gift of
M. Daemen) and standard ABC detection as described
elsewhere.13 Positively stained cells were
visualized with 3,3'-diaminobenzidine (Sigma), and slides were
counterstained with hematoxylin. The number of BrdU-stained cells and
total cells (estimated by counting nuclei) was counted per vessel cross
section (3 sections per rat). A replication index was calculated by
using the following equation: percent positive cells=number of
BrdU-positive nuclei per 3 cross sections/total number of nuclei per 3
cross sectionsx100.
Systolic blood pressures were taken as described
previously.5 In brief, individual conscious rats
were put into restrainers and conditioned to handling on two
consecutive days. Then SBPs were measured by tail-cuff plethysmography
(Narco Biosystems). Three measurements per animal were taken to obtain
a mean value for the day. For the baseline value, blood pressures were
measured 2 days before treatment and on days 0, 3, 4, 5, and 6 after
Ang II pumps had been implanted.
For type III mesenteric vessels, two nonconsecutive cross
sections (5 µm) were stained with the elastin fiber–specific
stain orcein, and cross-sectional areas were assessed by a computer
program (Optimus, BioScan, Edmonds, Wash). Cross-sectional-area was
determined by taking measurements between the external and internal
elastic laminas.
Values are given as mean±SEM. ANOVA was performed.
Comparisons of two group means were made with subsequent Fisher's
protected least-square difference test. P<0.05 was
considered significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Effect of Ang II on SBP
To study the mitogenic effect of Ang II on the
blood vessels in vivo, we used osmotic pumps to deliver Ang II
subcutaneously at a rate of 435 ng ·
kg-1 · min-1.
Compared with Ringer's-treated animals, SBPs from Ang II–treated
animals were significantly higher on days 3, 4, 5, and 6. Blood
pressure reached a peak of 200 mm Hg on day 6 in the Ang
II–treated group. Ringer's-infused animals did not show any
significant changes in blood pressure during the treatment period
(Figure 1). Hydralazine treatment
lowered SBP significantly. By day 6, hydralazine-treated
animals showed a mean SBP of 75 mm Hg in contrast to a mean SBP
of 120 mm Hg in the Ringer's-treated animals (Figure 1).
Cotreatment of Ang II–treated animals with hydralazine
inhibited the development of hypertension. SBP was 85 mm Hg in
animals infused with both Ang II and hydralazine on day 6
(Figure 1).
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[in a new window]
Figure 1. Blood pressure measurement (mean±SEM) in rats
receiving continuous subcutaneous infusion of Ang II, Ringer's, Ang II
plus hydralazine (AngII+Hyd), or Ringer's plus
hydralazine (Hyd+Ringer's) for 1 week. Ang II was given at 435
ng · kg-1 · min-1, and
hydralazine was infused at 26 mg ·
kg-1 · d-1. Ang II raised blood
pressure significantly, whereas hydralazine treatment abolished
the hypertensive effect of Ang II.
We examined two major branches in the mesenteric vascular
tree. The radial vessels, usually two branch levels from the superior
mesenteric artery, are classified as type III microvessels. Type I
vessels are the smallest, penetrating the gut (Figure 2
). ). Antihypertensive treatment
with hydralazine did not block this growth induced by Ang II
(Figure 3). Additionally, hydralazine treatment alone had no
effect on cross-sectional area when compared with that in Ringer's
control animals (Figure 3).
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[in a new window]
Figure 3. Bar graph showing cross-sectional area
measurements in type III microvessels. Animals were divided into four
treatment groups: Ang II, Ang II plus hydralazine (Ang II+hyd),
Ringer's, and Ringer's plus hydralazine (Ringer's+hyd). Ang
II was given at 435 ng · kg-1 ·
min-1, and hydralazine was infused at 26 mg
· kg-1 · d-1. ).
View larger version (135K):
[in a new window]
Figure 4. BrdU labeling of type I microvessels. A,
Micrograph of type I microvessel stained for BrdU from an Ang
II–treated animal. B, Micrograph of type I microvessel from an animal
receiving hydralazine and Ang II cotreatment. C, Micrograph of
type I microvessel from Ringer's -infused animal. D, Micrograph of
type I microvessel from an animal receiving Ringer's and
hydralazine cotreatment (x40 objective).
Rats were given Ang II and hydralazine to determine
their effects on DNA replication in the media of the carotid artery.
The drugs were infused via osmotic pumps for 1 week. At the end of the
week, the left carotid artery was fixed, histologically
processed, and stained for BrdU. Ang II treatment stimulated SMC DNA
replication in the media of the carotid artery (16-fold, Figure 5A; also see BrdU labeling in Figure 6). In rats infused with Ang II and
hydralazine, measurement of DNA replication showed no
significant difference from that in Ang II–infused animals
(P>0.05, Figure 5A). Despite the pressure-normalizing
effects of hydralazine, the increase of DNA replication in the
media of the carotid artery was not prevented. Thus, rats treated with
Ang II and hydralazine showed levels of DNA replication similar
to those found in animals receiving Ang II alone. Hydralazine
alone produced a replication index similar to that seen in Ringer's
animals (P>0.05).
View larger version (35K):
[in a new window]
Figure 5. DNA labeling by BrdU staining in blood vessels.
Control rats were infused with Ringer's (vehicle). Ang II was infused
at 435 ng · kg-1 · min-1.
Hydralazine (hyd) was given via osmotic pump at 26 mg ·
kg-1 · d-1. All rats also received
continuous infusion of BrdU for 1 week (via a separate pump) to label
replicating cells. Top, BrdU labeling index for SMCs of carotid
arteries. Bottom, BrdU labeling index for SMCs of type III
microvessels. Values are mean±SEM.
View larger version (147K):
[in a new window]
Figure 6. Medial SMC replication in carotid arteries. A,
Micrograph of carotid artery stained for BrdU from Ang II–treated
animal. B, Micrograph of carotid artery from animal receiving
hydralazine and Ang II cotreatment. C, Micrograph of carotid
artery from Ringer's-infused animal. D, Micrograph of carotid artery
from animal receiving Ringer's and hydralazine cotreatment
(x20 objective). 37-fold increase of DNA
replication versus that observed in the Ringer's animals (Figure 5B;
also see BrdU labeling in Figure 7).
View larger version (130K):
[in a new window]
Figure 7. Medial SMC replication in type III microvessel. A,
Micrograph of type III microvessel, stained for BrdU, from Ang
II–treated animal. B, Micrograph of type III microvessel from animal
receiving hydralazine and Ang II cotreatment. C, Micrograph of
type III microvessel from Ringer's-infused animal. D, Micrograph of
type III microvessel from animal receiving Ringer's and
hydralazine cotreatment (x20 objective). . The labeling index was 49.1±3.8% in
the Ang II–treated group. Again, hydralazine treatment did not
abolish this proliferative effect (64.0±6.6%; see Figure 8). The
Ringer's group of rats showed minimal cell replication.
View larger version (23K):
[in a new window]
Figure 8. Cumulative labeling of DNA replication in type I
microvessels. Rats were infused with Ang II (435 ng ·
kg-1 · min-1) or Ringer's (vehicle)
for 1 week. Hydralazine (hyd; 26 mg ·
kg-1 · d-1) was infused via an osmotic
pump subcutaneously. BrdU immunostaining was performed
and cell counting was done to generate replication index. Values are
mean±SEM.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Ang II, a potent vasoconstrictor, has been studied
extensively for its role in stimulating proliferation of SMCs. This
study was undertaken to determine whether Ang II could stimulate SMC
DNA replication in vivo in the absence of elevated pressure. We found
that Ang II stimulated SMC replication in the carotid arteries and type
I and III mesenteric microvessels, without elevated blood pressure.
Selected Abbreviations and Acronyms
Ang II
=
angiotensin II
bFGF
=
basic fibroblast growth factor
BrdU
=
bromodeoxyuridine
Ringer's
=
Ringer's lactate
SBP
=
systolic blood pressure
SMC
=
smooth muscle cell
TGF
=
transforming growth factor
Acknowledgments
This work was supported by National Institutes of Health
grants HL-07312 and DK-47659. The authors wish to acknowledge the
expert assistance of Patti Polinsky.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Mulvany MJ. Vascular growth in hypertension.
J Cardiovasc Pharmacol. 1992;20(suppl 1):S7–S11.
1-Adrenoreceptor blockade reduces the
angiotensin II–induced vascular smooth muscle cell DNA
synthesis in the rat thoracic aorta and carotid artery. Circ
Res. 1992;70:1122–1127.1-adrenoreceptor stimulation increases DNA synthesis
in rat arterial wall: modulation of responsiveness after
vascular injury. Arterioscler Thromb Vasc Biol. 1996;16:1122–1129.
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Y. E.G. Eskildsen-Helmond and M. J. Mulvany Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries Hypertension, April 1, 2003; 41(4): 891 - 897. [Abstract] [Full Text] [PDF]
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A. Virdis, M. F. Neves, F. Amiri, E. Viel, R. M. Touyz, and E. L. Schiffrin Spironolactone Improves Angiotensin-Induced Vascular Changes and Oxidative Stress Hypertension, October 1, 2002; 40(4): 504 - 510. [Abstract] [Full Text] [PDF]
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 M. W Manning, L. A Cassis, J. Huang, S. J Szilvassy, and A. Daugherty Abdominal aortic aneurysms: fresh insights from a novel animal model of the disease Vascular Medicine, February 1, 2002; 7(1): 45 - 54. [Abstract] [PDF]
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 C. Moreno, A. Lopez, M. T. Llinas, F. Rodriguez, A. Lopez-Farre, E. Nava, and F. J. Salazar Changes in NOS activity and protein expression during acute and prolonged ANG II administration Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R31 - R37. [Abstract] [Full Text] [PDF]
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J. Ibrahim, A. D. Hughes, and P. S. Sever Action of Angiotensin II on DNA Synthesis by Human Saphenous Vein in Organ Culture Hypertension, November 1, 2000; 36(5): 917 - 921. [Abstract] [Full Text] [PDF]
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K. Matrougui, Y. E. G. Eskildsen-Helmond, A. Fiebeler, D. Henrion, B. I. Levy, A. Tedgui, and M. J. Mulvany Angiotensin II Stimulates Extracellular Signal-Regulated Kinase Activity in Intact Pressurized Rat Mesenteric Resistance Arteries Hypertension, October 1, 2000; 36(4): 617 - 621. [Abstract] [Full Text] [PDF]
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H. Ueno, P. Kanellakis, A. Agrotis, and A. Bobik Blood Flow Regulates the Development of Vascular Hypertrophy, Smooth Muscle Cell Proliferation, and Endothelial Cell Nitric Oxide Synthase in Hypertension Hypertension, July 1, 2000; 36(1): 89 - 96. [Abstract] [Full Text] [PDF]
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E. Mervaala, D. N. Muller, F. Schmidt, J.-K. Park, V. Gross, M. Bader, V. Breu, D. Ganten, H. Haller, and F. C. Luft Blood Pressure-Independent Effects in Rats With Human Renin and Angiotensinogen Genes Hypertension, February 1, 2000; 35(2): 587 - 594. [Abstract] [Full Text] [PDF]
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E. A. Tallant, D. I. Diz, and C. M. Ferrario Antiproliferative Actions of Angiotensin-(1-7) in Vascular Smooth Muscle Hypertension, October 1, 1999; 34(4): 950 - 957. [Abstract] [Full Text] [PDF]
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W. B. Strawn, C. M. Ferrario, and E. A. Tallant Angiotensin-(1–7) Reduces Smooth Muscle Growth After Vascular Injury Hypertension, January 1, 1999; 33(1): 207 - 211. [Abstract] [Full Text] [PDF]
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