(Hypertension. 2000;36:89.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Blood Flow Regulates the Development of Vascular Hypertrophy, Smooth Muscle Cell Proliferation, and Endothelial Cell Nitric Oxide Synthase in Hypertension
From the Cell Biology Laboratory, Baker Medical Research Institute and Alfred Hospital, Melbourne, VIC, Australia.
Correspondence to Dr Alex Bobik, Cell Biology Laboratory, Baker Medical Research Institute and Alfred Hospital, St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail alex.bobik{at}baker.edu.au
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Abstract |
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Abstract—Blood flow participates in vascular remodeling during development and growth by regulating cell apoptosis and proliferation. However, its significance in the development of vascular hypertrophy and vascular remodeling in hypertensive patients is not known. We investigated how changing blood flow through the common carotid artery (CA) of young adult rats rendered hypertensive via aortic coarctation affects CA hypertrophy and/or remodeling responses to hypertension. Blood flow was reduced by
50% as a result of ligation of the
external CA immediately after hypertension was induced, and the effects
of that procedure were compared with those in similarly treated
normotensive rats. Reducing blood flow in the hypertensive animals
markedly augmented the development of CA hypertrophy over
the ensuing 14 days by increasing the vessel wall cross-sectional area.
In those animals, CA lumen size was unaltered by reducing blood flow,
as was CA structure in normotensive animals. The greater
hypertrophy in the hypertensive animals with reduced blood
flow was associated with enhanced smooth muscle cell (SMC)
proliferation 3 days after the hemodynamic changes were
induced. There also appeared to be more extensive remodeling of the
endothelium in the hypertensive animals with normal
flow; this was indicated by the greater frequency of apoptotic
endothelial cells at that time. This reduction in blood
flow also attenuated endothelial cell nitric oxide
synthase expression in hypertensive animals but not in normotensive
animals. Severe reductions in blood flow (90%) were required to
reduce endothelial cell nitric oxide synthase in the
normotensive animals. Increasing CA nitric oxide levels by
perivascular application of
S-nitroso-N-acetylpenicillamine (SNAP) to
the CAs of hypertensive animals with reduced
endothelial cell nitric oxide synthase attenuated the
greater SMC proliferation. Thus, reduced blood flow in hypertensive
animals promotes hypertrophy by enhancing SMC proliferation
via mechanisms that reduce the inhibitory effects of nitric
oxide on SMC proliferation.
Key Words: hypertension, experimental • blood flow • vascular hypertrophy • SNAP • apoptosis
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Introduction |
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Alterations in vascular structure are common in hypertension.1 2 In small arteries, the increase in vessel wall thickness/lumen (w/l) ratio contributes to greater vascular reactivity and elevated blood pressure,2 and in large arteries, a thicker wall is also a major risk factor for atherosclerosis.3 4 Two processes, vessel remodeling1 5 and/or vessel hypertrophy,1 2 6 are responsible for these changes in arterial structure. Vessel remodeling occurs through reorganization of apparently existing cellular and extracellular components around a smaller lumen.1 In contrast, hypertrophy involves vascular smooth muscle cell (SMC) proliferation, hypertrophy, and/or polyploidy,1 6 in addition to extracellular matrix deposition,7 which may be localized to the outer and/or inner regions of the wall or may occur throughout the vessel wall.1
The underlying mechanisms of vascular structural alterations are poorly understood. Vasoactive substances and hormones such as angiotensin II2 have been implicated, and studies in culture suggest that the mechanical deformation of endothelial cells (ECs) and SMCs is important.8 9 Pulsatile stretch of cultured SMCs or ECs stimulates their proliferation8 9 10 and growth factor production.9 Because blood flow can also change in hypertension,11 alterations in shear stress might also contribute to vascular structural changes. Continuous or pulsatile shear stress on cultured ECs modulates growth factor genes, including fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-B (PDGF-B).12 In cultured ECs nitric oxide synthase (eNOS) is also elevated by fluid shear stress,13 and its product (nitric oxide) can inhibit both SMC proliferation14 and migration.15
Recent studies16 in vivo indicate that reductions in shear stress induced by greatly reducing blood flow in the carotid artery (CA) of immature normotensive animals stimulates CA remodeling by altering EC and SMC apoptosis and proliferation rates. We investigated how more moderate reductions in blood flow affect CA structure in animals with developing hypertension. In the hypertensive animals, reductions in blood flow augmented the developing vessel wall hypertrophy without affecting lumen size (ie, there was no evidence of remodeling) via mechanisms that enhance SMC proliferation in the media and frequently in the intima. A reduction in nitric oxide production resulting from decreased eNOS expression appears responsible.
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Methods |
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Animals and Experimental Design
Male Sprague-Dawley rats weighing 350 to 450 g from the Institute’s Biology Research Unit were used in this study. The animals were divided into 2 groups. The rats in one group were rendered hypertensive via aortic coarctation, and those in the other group underwent sham operation. In approximately one half of the animals in each group, the left external CA was ligated to reduce left common CA blood flow, and the remaining rats underwent sham operation. Blood pressure, blood flow, CA morphological factors, left ventricular weight (mg)/body weight (g) ratio (LV/BW), indices of proliferation and apoptosis, and the expression of eNOS and FGF-2 were examined 3 and/or 14 days after surgery. The CAs of some hypertensive animals with reduced blood flow were treated with S-nitroso-N-acetylpenicillamine (SNAP) applied perivascularly. In a subgroup of hypertensive and normotensive animals, the effects of severe reductions in blood flow (such as that produced by also ligating the internal CA) on eNOS were also examined. This study was approved by the Baker Institute Experimentation Committee.
Operations
Coarctation of the abdominal aorta was performed as previously
described.17 The animals were anesthetized with
ketamine (80 mg/kg) and xylazine (10 mg/kg IP), and a
laparotomy was performed to expose the abdominal aorta. A silk ligature
(size 3-0) was then tied around the aorta between the 2 renal arteries,
and a standardized coarctation was produced by means of a stainless
steel wire 0.4 mm in diameter. In the animals that underwent sham
operation, the ligature was not tied. Carotid artery blood flow in half
the sham-operated (normotensive) animals and in those with aortic
coarctations (hypertensive animals) was reduced during surgery by
ligation of the left external CAs.16 Greater reductions in
blood flow (90%) were achieved when necessary by also ligating the
internal carotid artery.18
S-nitroso-N-acetylpenicillamine (SNAP) (1
mmol/L in 40% pluronic gel, 1 mL) was also applied perivascularly
to CAs of some hypertensive animals with reduced blood flow during
surgery as we have described19 ; only the gel
was applied to control animals.
CA Blood Pressure and Blood Flow
Intra-arterial systolic blood pressure (SBP)
was measured via a catheter inserted into the right external CA in rats
that had been anesthetized with ethyl carbonate (urethane,
1.5g/kg IP). In some animals, the right femoral artery SBP was also
measured in a similar manner. SBP was recorded for 30 minutes by
means of a Grass Recorder (Grass Instruments) and was averaged. The
left common CA blood flow was measured for 30 minutes by means of an
ultrasonic Doppler flow probe (Transonic Flow probe 2SB1167,
Transonic Systems, Inc) connected to a transit-Time-Flow-Meter
(Transonic Systems, Inc), and the readings were averaged.
Vessel Collection and Processing
CAs were isolated and were processed as described
previously.19 20 The rats were deeply anesthetized
with sodium pentobarbitone (100 mg/kg body wt), and the vessels were
perfusion fixed in situ with 4% paraformaldehyde in
0.1 mol/L sodium phosphate buffer (PBS, pH 7.4) at the animal’s SBP
reading. The CAs were dissected into proximal and distal
sections, were postfixed in osmium tetroxide, and were embedded in
Epon.20 Arteries for immunohistochemical study were
perfused with saline, mounted in optimal cutting temperature compound
(OCT) (Tissue Tek), and stored at -80°C.19
Vessel Morphometry
CA morphologic characteristics were assessed by means of
Epon-embedded sections 1 µm thick that were stained with 1%
toluidine blue in 1% borax.6 20 The media was defined as
the region between the internal and external elastic laminae, the
intima area was defined as the region between the
endothelium and the internal elastic laminae, and the
lumen area as the area encompassed by the endothelium.
The morphometric result for each vessel is the average of
measurements from its proximal and distal regions.
Immunohistochemistry and Cell Proliferation
FGF-2 and eNOS expression was assessed by
immunohistochemistry.19 20 Briefly, 6 µm cross
sections of arteries were postfixed in 4%
paraformaldehyde (pH 7.4), were treated with 3%
H2O2 in PBS, and were
incubated with 10% horse serum in 0.1 mol/L PBS (pH 7.4) before
application of the primary antibody, which was either an anti-FGF-2
antibody [anti-human monoclonal antibody (1:1000), du Pont du Nemours
and Company, (#DE6)] or an anti-eNOS antibody [mouse anti-human
monoclonal antibody (1:1000), (Transduction Laboratories) (#N30020)].
After having been washed, the sections were incubated with the
biotinylated anti-mouse IgG [Zymed Laboratories, (#61-1640) or a
biotinylated anti-goat IgG (Vector Laboratories Inc) (#BA-2001], both
of which were diluted 1:200. Antigenic peptides were detected by means
of the avidin-biotin-peroxidase complex method (Vector Laboratories
Inc) with 3,3'-diaminobenzidine tetrachloride as the chromogen.
Sections were counter-stained with hematoxylin. A semiquantitative
assessment of relative intensity of expression of the immunoreactive
peptides was carried out as described by Ishikawa et al.21
The system of graded intensities21 from 0 to 4+ was used;
the symbol – represented no staining; 1+, weak staining;
2+, moderate staining; 3+, intense staining; and 4+, very intense
staining. The numbers of proliferating ECs and SMCs were estimated from
the percentage of cells expressing proliferating cell nuclear antigen
(PCNA),22 which was detected with a mouse monoclonal
anti-PCNA (1:200) clone PC-10 [Santa Cruz Biotechnology, Inc.,
#sc-56]; a mouse IgG1 was used as a control. Positive cells were
detected by means of a biotinylated anti-mouse IgG (1:200) and the
avidin-biotin-peroxidase complex method.19 20 The cells
were counterstained with hematoxylin. No fewer than 300 nuclei of SMCs
and 100 nuclei of ECs were counted.
TUNEL-Positive Cells
Terminal deoxynucleotidyl transferase
mediated dUTP-X nick end labeling (TUNEL) of cells was performed on
6 µm cross-sections postfixed in 4%
paraformaldehyde (pH 7.4).23 24 The
sections were briefly irradiated with microwaves and were placed in 0.1
mol/L Tris-HCl containing 3% BSA and 20% normal bovine serum (pH
7.5). Terminal deoxynucleotidyl transferase enzyme
and dUTP-X were used according to the manufacturer’s specifications
(in situ death detection kit, #1684817, Boehringer-Mannheim).
Annexin V binding and labeled DNA nicks were detected by means of a
peroxidase-coupled monoclonal antibody against fluorescein
(converter-POD, #1684817, Boehringer-Mannheim),
3,3'-diaminobenzine, and
H2O2.24 Nuclei
were counterstained as before, and TUNEL-positive cells were
counted.
Statistical Analysis
Data are presented as mean±SEM. Differences between
groups were analyzed via 1-way ANOVA after testing for
normality by means of the Kolmogorov-Smirnov test (Sigmastat, Jandel
Scientific)19 ; the Newman Keuls test was used for
post hoc analyses. Data failing the normality test were
analyzed by nonparametric analysis of
variance, and where differences were detected, the Mann-Whitney rank
sum test was used to determine significance.19 The
expression of eNOS, and FGF-2 was also analyzed in this manner.
P<0.05 was considered significant.
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Results |
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BW and Hemodynamics
Three days after the operations had been performed, CA SBP in the rats with aortic coarctation was
63 mm Hg higher than that in
the normotensive rats that underwent sham operation
(P<0.05; Table 1). At
that time, the differences in SBP across the coarctation in the
hypertensive animals, which were reflected by differences in pressure
between the carotid and femoral arteries, were 60 mm Hg in the
hypertensive normal blood flow animals and the hypertensive reduced
blood flow animals (n=3 per group). There were no significant
differences in SBPs in the animals with normal or reduced left CA blood
flow (P>0.05; Table 1), and there was also no
difference in heart rate (P>0.05, Table 1).
LV/BW ratios were increased in the hypertensive animals 9% to 18%
(P<0.05; Table 1). LV/BW in the hypertensive reduced
blood flow animals was 8% greater than that in the hypertensive normal
blood flow group (P<0.05). Left CA blood flow in
normotensive animals with ligated external CAs was reduced by
>50%, and in hypertensive animals it was reduced by 40% (both,
P<0.05). There was no difference in CA blood flow between
the normotensive normal blood flow group and the hypertensive normal
blood flow group (P>0.05; Table 1). Two weeks after
the sham aortic operation, SBP was 20 to 30 mm Hg higher than it
was 3 days after the operation (P<0.05), but LV/BW ratios
and heart rates were unaltered (Table 1). SBPs in the
hypertensive animals were identical to those 3 days after the
operation, and increases in LV/BW ratios were small (Table 1).
CA blood flow increased slightly during the 2 weeks after the external
CA was ligated in the normotensive animals, but in hypertensive reduced
blood flow animals, there was a small decrease in CA blood flow (Table 1).
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CA Structure
The left CA cross-sectional wall area (CAWA; ie, media plus
intima) of the normotensive normal blood flow animals 3 and 14 days
after their operations was similar (0.0718 versus 0.0716
mm2; Figure 1), and
all other comparisons were made with these animals that underwent sham
operation. Reducing blood flow for 3 days in normotensive animals did
not significantly affect the CAWA (P>0.05); the CAWA was
also unaffected when blood flow was reduced for 14 days
(P>0.10; Figure 1). Three days after hypertension
was induced, the CAWA was 9% higher than in normotensive normal
blood flow animals, but the difference was not significant
(P>0.05). After 14 days of hypertension in the hypertensive
normal blood flow group, the CAWA was increased by 45% (normotensive
normal blood flow group, P<0.05). In the hypertensive
reduced blood flow group, the increase in CAWA 3 days after the CA
blood flow was reduced averaged 39% (normotensive normal blood
flow group, P<0.05) and was similar to that of the CAWA
observed in the hypertensive normal blood flow group in which the
animals were hypertensive for 14 days (39% versus 45%;
P>0.05; Figure 1). The increases in CAWA were also
time dependent in the hypertensive reduced blood flow group (Figure 1), and after 14 days, the CAWAs were 80% greater than in
normotensive normal blood flow group animals (P<0.05). In
addition, in one third of the left common CAs, a significant smooth
muscle–rich intima developed (Figure 2),
which was not observed in any of the hypertensive normal blood flow
animals or the normotensive reduced blood flow animals (Figure 2). Neither the reduction in flow nor its combination with
hypertension significantly affected CA lumen size (P>0.10,
Figure 1). Thus hypertrophy of the CA wall is the
only contributor to the increase in calculated CAWA/lumen
cross-sectional area (Wa/La) ratio, which averaged 0.36 and 0.28 in
hypertensive reduced blood flow animals and hypertensive normal blood
flow animals, respectively. The Wa/La was similar in the normotensive
animals and averaged 0.22 and 0.22 in normotensive normal blood flow
animals and normotensive reduced blood flow animals, 14 days after
operation.
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3 days after induction of
hemodynamic changes in hypertensive reduced blood flow
animals, P<0.05.
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Vascular Cell Proliferation and Apoptosis
Because changes in vessel structure in normotensive and
hypertensive animals can involve cell proliferation and/or
apoptosis,16 24 25 we investigated how reductions
in blood flow during the development of hypertension affected those
processes. Reductions in CA blood flow did not significantly affect the
frequency of PCNA positive ECs in normotensive animals
(P>0.05; Figure 3). However,
PCNA frequency in ECs was increased by hypertension, and 3 days after
operation averaged nearly 8% in the hypertensive groups. PCNA was
barely detectable in the ECs of the normotensive normal blood flow
group (P<0.05; Figures 3 and 4). After 2 weeks of hypertension, PCNA
frequency in ECs was reduced by 50% (Figure 3). Three days
of hypertension also increased the frequency of TUNEL positive ECs in
the left CA (Figure 4); this was greatest in the hypertensive
normal blood flow group, which averaged 19%
(P<0.05; Figure 3). Thereafter, the frequency of
TUNEL-positive ECs decreased below 5% (Figure 3), despite
continuing high blood pressure (Table 1). In the normotensive
normal blood flow groups, <2% of the ECs were TUNEL positive, and an
apparent increase in TUNEL-positive ECs in the normotensive reduced
blood flow animals was not significant (from normotensive reduced blood
flow animals, P>0.05).
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Reductions in blood flow in hypertensive animals markedly increased the
frequency of PCNA-positive SMCs in the CAs and averaged 19% in
hypertensive reduced blood flow animals 3 days after the
hemodynamic changes were induced (P<0.05;
Figure 4). At 2 weeks after operation, the frequency of PCNA
positive SMCs in the hypertensive animals was similar to that in
normotensive normal blood flow animals (1%) (Figure 3).
Reducing blood flow in the normotensive animals for 3 days caused a
very small and not significant increase in PCNA-positive cells
(P>0.05; Figure 3). The frequency of TUNEL-positive
SMCs in the CA of hypertensive animals was below 5%, as were any small
flow-induced changes (Figure 4). Thus SMC proliferation is a
major contributor to greater CA hypertrophy when blood flow
is reduced in those with hypertension.
Effect of Flow and Hypertension on eNOS Expression
Because eNOS is increased by angiotensin
II26 and because it can be regulated by both pressure and
shear stress27 and its product, nitric oxide, inhibits
SMC proliferation14 and migration,15 we also
examined how the expression of eNOS in the CA was altered by flow
during hypertension. In normotensive animals, eNOS was unaffected by a
3-day 50% reduction in blood flow; rather, reductions were observed
only when blood flow was very low (90% reduction,18
Table 2 and Figure 5, left). Expression was highest in
hypertensive normal blood flow animals, in which eNOS was 50%
greater than in the normotensive normal blood flow group (Table 2; Figure 5, left). When blood flow was reduced
50% in hypertensive animals, eNOS levels were, on average,
approximately one half of those in hypertensive normal blood flow
animals (for difference, P<0.05; Table 2 and Figure 5, left). The eNOS in those animals also tended to be lower than
in corresponding normotensive animals. Thus moderate reductions in
blood flow attenuate eNOS expression in hypertensive animals but not in
normotensive animals and could contribute to the flow-mediated increase
in SMC proliferation.
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Vessel NO Increases and SMC Proliferation in Hypertension
To determine whether increasing NO levels in CAs of hypertensive
reduced blood flow animals attenuates SMC proliferation, the NO donor
SNAP was also applied at surgery to the CA, and proliferation was
assessed 24 hours later. In CAs treated with SNAP, only 13.6±2.3% of
the SMCs were PCNA positive, compared with PCNA positivity of
30.6±2.6% in controls (P<0.05; Figure 6). SBP was unaffected by SNAP and
averaged in those 2 groups 149±8 and 146±7 mm Hg, respectively
(P>0.05).
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Fibroblast Growth Factor-2 Expression
Because FGF-2 has been associated with increased eNOS
expression28 and can induce SMC proliferation in
vivo,29 we compared its expression in the CA of the
normotensive and hypertensive animals 3 days after
hemodynamic changes were induced. FGF-2 was present
in CA ECs of the normotensive normal blood flow animals, but in the
normotensive reduced blood flow animals, it was mostly absent (Table 2 Figure 5, right). High amounts of FGF-2 were
present in the ECs of hypertensive normal blood flow animals,
substantially more so than in ECs of the hypertensive reduced blood
flow group (P<0.05). FGF-2 in CA media of hypertensive and
normotensive animals was similar (Table 2, Figure 5, right).
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Discussion |
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Complex responses of ECs and SMCs to vasoactive agents and blood pressure are major determinants of vascular hypertrophy in hypertension. We have demonstrated that blood flow also regulates vascular hypertrophy. A moderate reduction in CA blood flow during the development of hypertension further increases CA hypertrophy without inducing vessel remodeling by altering the pattern of SMC and EC proliferation and apoptosis. The greater hypertrophy is primarily due to greater SMC proliferation, which is probably a consequence of removal of NO inhibitory effects on SMC proliferation and migration. In the hypertensive animals, blood flow reductions did not alter FGF-2, but rather decreased the expression of eNOS, the product of which (NO) can prevent SMC proliferation14 and migration.15 In contrast, in normotensive animals, similar reductions in flow affected neither eNOS expression nor CA structure.
Fluid shear stress and circumferential stretch contribute to normal
vessel geometry and can contribute to the pathological changes in
vascular structure associated with hypertension and
atherosclerosis.7 Short-term cyclic
stretch in vitro induces ECs to proliferate10 and to
produce platelet-derived growth factor-B (PDGF-B),12
and shear stress on cultured ECs stimulates FGF-213 and
eNOS production.14 Our studies indicate that an
increase in the circumferential stretch of ECs also appears important
for their proliferation in vivo during the development of vascular
hypertrophy. Early in the development of CA
hypertrophy, PCNA was expressed in 8% of the ECs,
but was barely detectable in the ECs of normotensive animals; it did
not appear to be influenced by the reduction in blood flow. Because
vessel lumen size was not altered by either hypertension or the
reduction in blood flow, the increase in endothelial
cell PCNA expression in the hypertensive vessels probably reflects a
modification of endothelial structure associated with
developing vessel hypertrophy. The finding of an increase
in TUNEL-positive ECs during the development of vascular
hypertrophy suggests a process of
endothelial remodeling that also involves the loss of
ECs as a result of apoptosis. Recently, a cycle involving cell
proliferation-migration-loss has been reported during remodeling of EC
monolayers in vitro.30 At present, one can only
speculate about the mechanism responsible for the higher
apoptosis of ECs in the vessels undergoing
hypertrophy. Oxidant stress can be elevated in those with
hypertension,31 and it is possible that hydrogen peroxide,
a potent stimulant of EC apoptosis, is
involved.32
Our findings on eNOS in ECs of the vessels undergoing hypertrophy suggest an active involvement of the endothelium in regulating the development of vascular hypertrophy in hypertensive animals. Nitric oxide limits mitogenic responses of cultured SMC14 and also their in vitro migratory ability.15 Our finding that a moderate reduction in blood flow in the hypertensive animals markedly reduces eNOS and augments vascular hypertrophy is consistent with the theory of a growth inhibitory role of NO in hypertension. The observed reduction in eNOS may also account for the development of the SMC-rich intima in many of the hypertrophied CAs of the hypertensive reduced blood flow animals, which is an effect dependent on SMC migration from the media to the intima. The lack of any similar flow-dependent reductions in eNOS in CA of normotensive animals is consistent with these mechanisms and suggests that the endothelium of hypertensive animals is more responsive to changes in blood flow.
Smooth muscle cell proliferation is a major mechanism responsible for the greater CA hypertrophy in the hypertensive animals with reduced blood flow, because apoptosis of SMCs, although apparent, was not substantially affected; in adult spontaneously hypertensive rats, a resistance of SMCs to apoptosis has been implicated in vascular hypertrophy.25 The observed increases in SMC proliferation in the CA of the hypertensive animals is consistent with the contribution of circulating angiotensin II to vascular hypertrophy. Plasma renin activity is increased in animals with aortic coarctations,33 and their vascular hypertrophy can be prevented with an angiotensin II receptor antagonist.34 Also, angiotensin II stimulates SMC proliferation in CAs.35 Although angiotensin II-induced SMC proliferation in vivo appears dependent on FGF-2,36 and in culture angiotensin II elevates FGF-2 expression in SMCs,37 we did not observe any FGF-2 elevation in the SMCs of the hypertensive animals. Whether increased release of FGF-2 from cells in the CA or an increase in another growth factor stimulated by angiotensin II accounts for SMC mitogenesis in hypertensive animals remains to be determined.
In summary, our study has demonstrated that in young adult hypertensive animals, moderate reductions in blood flow (less than those reported to induce vessel remodeling in normotensive animals)16 27 further augments vascular hypertrophy by elevating SMC proliferation. This effect appears to be due to withdrawal of the inhibitory effects of nitric oxide on SMC proliferation and migration during the development of vessel hypertrophy, a consequence of reduced eNOS expression. Such a mechanism may contribute to the development of a significant SMC-rich intima in many hypertrophied CAs, which in humans is a major risk factor for stroke.4
Received December 20, 1999; first decision January 4, 2000; accepted January 27, 2000.
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