(Circulation. 1999;100:2267.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Resistance Artery Mechanics, Structure, and Extracellular Components in Spontaneously Hypertensive Rats
Effects of Angiotensin Receptor Antagonism and Converting Enzyme Inhibition
From the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}IRCM.qc.ca
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Abstract |
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Background—Altered vascular mechanics resulting from changes in collagen and integrins may influence resistance artery structure and function and, therefore, peripheral resistance and blood pressure in spontaneously hypertensive rats (SHR).
Methods and Results—Effects of age,
angiotensin-converting enzyme inhibition (fosinopril, 10 to
30 mg/kg per day), and AT1-receptor antagonism
(irbesartan, 50 mg/kg per day) on vascular structure, mechanics, and
composition were assessed in SHR. Systolic blood pressure was
elevated in young SHR (130±2 mm Hg) compared with Wistar-Kyoto
(WKY) rats (106±2 mm Hg). In adult SHR, the rise in
systolic blood pressure (44±3 mm Hg) was blunted by
fosinopril (18±1 mm Hg) and irbesartan (9±3 mm Hg). Lumen
diameter of mesenteric resistance arteries was smaller and media/lumen
ratio was greater in young and adult SHR versus WKY rats. Growth index
was 24% in untreated adult SHR versus WKY rats; these values were
-35% for fosinopril-treated and -29% for irbesartan-treated SHR
versus untreated SHR. Isobaric wall stiffness was normal despite
increased stiffness of wall components in adult SHR vessels. Irbesartan
partially prevented stiffening of wall components in SHR. The
collagen/elastin ratio was greater in adult SHR vessels (6.5±1.3) than
in WKY (3.2±0.4) vessels. Expression of
vß3 and 5ß1
integrins was increased in SHR aged 20 versus 6 weeks. Expression of
5ß1 integrins was lower in young SHR, and
vß3 integrins were overexpressed in adult
SHR versus WKY rats. Irbesartan and fosinopril attenuated differences
in the collagen/elastin ratio and integrin expression.
Conclusions—Wall components of mesenteric resistance arteries stiffen with age in SHR. Interrupting the renin-angiotensin system has normalizing effects on integrin expression and composition, stiffness, and growth of the arterial wall.
Key Words: arteries • mechanics • remodeling • collagen • cell adhesion molecules
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Resistance arteries of spontaneously hypertensive rats (SHR) undergo a combination of hypertrophic (increased media thickness and cross-sectional area) and eutrophic (decreased lumen and external diameters with unaltered media cross-sectional area) remodeling.1 2 3 Changes in small artery mechanics may also influence pressure-diameter relations of blood vessels.4 Opposing changes in wall stiffness occur with aging in different arterial beds in hypertensive rats. Increased distensibility of cerebral arterioles from 6- to 8-month-old stroke-prone SHR (SHR-SP) was absent in younger (3- to 4-month-old) SHR-SP,5 suggesting that prolonged hypertension increases pial arteriole compliance and decreases geometry-independent wall stiffness6 despite vascular hypertrophy. Decreased vascular stiffness is not a global response to prolonged hypertension. In 2-kidney 1-clip renal hypertensive rats, carotid arteries were stiffer after 9 and 24 weeks, but at 1 and 5 weeks after renal artery clipping, no stiffening had occurred. With chronic exposure to high blood pressure, carotid arteries in this model stiffen,7 whereas in SHR-SP, pial arterioles become less stiff.
Vascular stiffening may involve changes in wall composition. An
increased proportion of more distensible (smooth muscle and elastin) to
less distensible (collagen and basement membrane) elements may underlie
decreased pial arteriolar stiffness in SHR-SP.6 Vascular
stiffness may also be modulated by adhesion molecules. Integrins,
physical connectors between the extracellular matrix and cytoskeleton,
also mediate signal transduction. They are composed of noncovalently
linked and ß subunits, the interaction of which dictates ligand
specificity. On the basis of the broad spectrum of integrin functions,
vascular remodeling and/or stiffening probably involves changes in
these anchorage sites. For example, fibronectin and its receptor, the
5ß1 integrin, may
modulate aortic stiffness in SHR.8
We hypothesized that age-related modifications in media components
and/or integrins define resistance artery abnormalities in SHR.
Specifically, we proposed that with aging in SHR, mesenteric resistance
arteries stiffen in association with increased collagen deposition and
integrin expression. To study the latter, we used
125I-echistatin, a 49–amino acid peptide found
in venom of Echis carinatus, and its ability to bind
vß3 integrins and
possibly other Arg-Gly-Asp (RGD)-binding integrins in a nondissociable
manner.9 We also tested whether antihypertensive
treatment with an AT1-angiotensin
receptor antagonist (irbesartan) or an
angiotensin-converting enzyme inhibitor
(fosinopril) would ameliorate hypertension-related differences in
artery wall stiffness, media components, and integrin profile.
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Methods |
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Animals
The present study was conducted according to recommendations from the Animal Care Committee of the Clinical Research Institute of Montreal and the Canadian Council of Animal Care. Male SHR and Wistar-Kyoto (WKY) rats were obtained from Taconic Farms (Germantown, NY) and housed under a 12-hour light/dark cycle at 22°C and 60% humidity. Starting at 10 weeks, rats were fed powdered diets (Purina Chow) containing fosinopril (10 mg/kg per day for 6 weeks and, because of minor blood pressure lowering, 30 mg/kg per day for 4 weeks), irbesartan (50 mg/kg per day), or neither drug until the age of 20 weeks. Irbesartan and fosinopril were provided by Dr James Powell (Bristol-Myers Squibb, Princeton, NJ). Systolic blood pressure (SBP) was measured at 2-week intervals by the tail-cuff method.10
Preparation of Small Arteries
Rats were killed at 6 or 20 weeks of age by decapitation, and
mesenteric vasculature was isolated.10 A third-order
artery (
2 mm) was placed on 2 glass microcannulas in a pressure
myograph and adjusted so that vessel walls were parallel without
stretch.11 Vessels were equilibrated (1 hour) under
constant intraluminal pressure (45 mm Hg) with warm (37°C)
physiological salt solution (PSS), which was
bubbled with 95% air and 5% CO2 to achieve a pH of
7.4 to 7.45. Vessels were used if they constricted >50% in response
to potassium (125 mmol/L KCl) with norepinephrine
(10-5 mol/L) and to norepinephrine
alone (10-5 mol/L). Endothelial
integrity was confirmed if acetylcholine (10-5
mol/L) relaxed precontracted vessels >75%.
Vascular Morphology
Vessels were deactivated by perfusing with
Ca2+-free PSS containing 10 mmol/L EGTA for
30 minutes. Lumen and media dimensions were measured with the
intraluminal pressure maintained at 45 mm Hg.
Vascular Mechanics
Intraluminal pressure was raised to 140 mm Hg 3 times, and
arteries were unbuckled by adjusting the cannulas. Intraluminal
pressure was increased stepwise10 to 140 mm Hg, and
media and lumen dimensions were measured at 5 points. Initial diameter
was measured at 3 mm Hg. If the vessel collapsed, lumen diameters
at 10 to 140 mm Hg were fit to a third-order polynomial equation,
and initial diameter was estimated.
Morphological and Mechanical Formulas
For definitions of parameters, see Reference 1212 .
Media cross-sectional area is calculated as
(
/4)x(De2-Di2),
where De and Di are
external and lumen diameters, respectively. Incremental distensibility
is calculated as (1/
P)x(D/D)x100=fractional change in lumen
diameter (D/D) per change in intraluminal pressure (P).
Circumferential strain (
) is
(D-Do)/Do, where D is the
lumen diameter for a given intraluminal pressure, and
Do is the original diameter at 3 mm Hg.
Circumferential stress (
) is (PD)/(2M), where P is the intraluminal
pressure (dyne/cm2), and D and M are lumen
diameter and media thickness, respectively. Elastic modulus was
determined by fitting stress-strain data to
=oeß, where
o was stress at Do and
ß is a constant related to the rate of increase of the stress-strain
curve. Tangential elastic modulus (ET) was calculated at several values
of stress from the derivative of the aforementioned exponential curve:
ET=d/d=ßoeß.
Remodeling index is calculated as
100x[(Di)n-(Di)remodel]/[(Di)n-(Di)h],
where (Di)n and
(Di)h were lumen diameters
of normotensive and hypertensive vessels, respectively, and
(Di)remodel is
[(De)h2-(4xCSAn/)]0.5,
where (De)h is the external
diameter of hypertensive vessels and CSAn is the
cross-sectional area of normotensive vessels.13 Growth
index is calculated as
(CSAh-CSAn)/CSAn,
where CSAn and CSAh are
media cross-sectional areas of normotensive and hypertensive vessels,
respectively.14
Determination of Resistance Artery Wall Composition
Deactivated arteries were pressurized at 45 mm Hg
and processed for electron microscopy.15 Electron
micrographs (final magnification x12 000) of 12 to 15 sections per
vessel were obtained with a JEM-1200EX electron microscope (JEOL Ltd)
and scanned (ScanJet 4C/t, Hewlett-Packard), and areas occupied by
smooth muscle cells, collagen, and elastin were measured by repeated
tracing using Adobe Photoshop 3.0.
Determination of RGD-Binding Integrins in Mesenteric Arteries of
SHR and WKY Rats
Proteins were extracted from frozen mesenteric vasculature in
lysis buffer containing (mmol/L) HEPES (pH 7.4) 50, NaCl 150,
MgCl2 1.0, CaCl2 1.0,
pepstatin 0.005, leupeptin 0.01, and
phenylmethylsulfonylfluoride 1.0, along with Nonidet P-40 1%
and aprotinin 50 KIU/mL. Proteins (10 µg) were incubated with
125I-echistatin (200 000 cpm), 5 mmol/L
MnCl2, and 50 mmol/L HEPES (pH 7.4) for 90
minutes at 25°C. Complexes were separated, without boiling and under
nonreducing conditions, by 6% SDS-PAGE. Gels were dried (2 hours,
80°C). Band intensity was quantified by PhosphorImager (Molecular
Dynamics) analysis.
Identification of RGD-Binding Integrins
After electrophoresis,
125I-echistatin·integrins were transferred to a
nylon membrane, which was immediately subjected to
autoradiography for band localization. The membrane was
blocked (0.05% Tween, 10% goat serum, 1% polyvinylpyrrolidone, and
2.5% to 5% milk), washed, and incubated with mouse anti-human
integrin v (1:500, Chemicon International
Inc), mouse anti-rat integrin ß3 (1:1000,
Pharmingen Canada), rabbit anti-human integrin
5 (1:2500, Chemicon International Inc), or
hamster anti-rat integrin ß1 (1:200, Pharmingen
Canada). Membranes were washed in PBS and treated with the appropriate
secondary antibody. Goat anti-mouse (1:10 000) and anti-rabbit
(1:20 000) antibodies were conjugated with horseradish peroxidase.
Membranes treated with goat anti-hamster antibody (1:1000) were exposed
to streptavidin peroxidase conjugate (1:1000) for 30 minutes. Signals
were detected by chemiluminescence.
Data Analysis
Data are presented as mean±SEM. Unpaired Student
t test (young rats) and 1-way ANOVA followed by a
Student-Newman-Keuls test (adult rats) (or Mann-Whitney test and
Kruskal-Wallis tests, respectively, where standard deviations were
different) and ANOVA for repeated measures were used as appropriate.
Interaction means were analyzed for "simple main effects"
by Student t test for unpaired data (young rats) and
Student-Newman-Keuls (adult rats) test. A value of P<0.05
was considered significant.
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Results |
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Body Weight, Blood Pressure, and Small Artery Morphology
Body weights were lower in SHR than in age-matched WKY rats.10 15 SBP was slightly elevated in young SHR (Table 1
), whereas in adult SHR, SBP was
significantly higher than in age-matched WKY rats (Figure 1). Between 10 and 20 weeks of age, SBP
rose significantly in untreated SHR but to a lesser degree
(P<0.01) in SHR treated with irbesartan and fosinopril
(Figure 1 and Table 2).
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P<0.05 vs untreated SHR. Bottom, Growth index of
mesenteric arteries in SHR showing untreated SHR vs WKY and irbesartan-
or fosinopril-treated SHR vs untreated SHR.
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Lumen and external diameters were smaller (Figure 2), media/lumen ratio was greater, and
media cross-sectional area was similar in vessels from SHR versus
age-matched WKY rats (Table 2
). In adult but not young SHR,
media width was greater in SHR than in WKY vessels. Irbesartan reduced
media width and media/lumen ratio, and fosinopril reduced media width
and media cross-sectional area in adult SHR vessels (Tables 1 and 2).
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6). Error bars indicate SEM.
*P<0.05 vs age-matched WKY rats.
In adult SHR, remodeling and growth indices were 88% and 24%,
respectively (Figure 1), measured at an intraluminal pressure of
45 mm Hg. These represent percentages of the difference
in lumen diameter between hypertensive and normotensive vessels that
are attributable to eutrophic remodeling and to growth. Irbesartan and
fosinopril produced hypotrophy resulting in growth indices of -29%
and -35%, respectively, relative to untreated SHR vessels.
Vascular Mechanics
Increasing intraluminal pressure to 140 mm Hg decreased the
media/lumen ratio of relaxed vessels from young and adult SHR and WKY
rats to similar degrees (data not shown) without altering media
cross-sectional area, since the media is incompressible (Figure 2). Lumen and external diameters expanded less with increasing
pressure in SHR versus WKY rats (Figure 2), indicating reduced
capacity for passive dilation in mesenteric arteries from SHR
irrespective of age. Distensibility was normal at
physiological pressures (40 to 140 mm Hg,
Figure 3) in SHR arteries, suggesting
that when collagen has been recruited, distensibility is so low that
media thickening does not lower it further.
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Increasing intraluminal pressure increased media stress more in WKY
than in SHR arteries (P<0.05), regardless of age (Figure 3). The stress-strain curve was shifted leftward in mesenteric
arteries from SHR compared with those from age-matched WKY rats (Figure 3).
When plotted against intraluminal pressure or stress, incremental
elastic modulus (wall stiffness) was similar between young WKY and SHR
arteries (Figure 4, Table 1). In
adult SHR, however, the slope of the incremental elastic modulus versus
stress was augmented (Figure 4, Table 2). Pressure is
transduced to the vessel wall as stress differentially depending on
vessel geometry; thus, the relation between elastic modulus versus
stress indicates stiffness of wall components (such as elastin,
collagen, and smooth muscle cells) independent of geometry. The
isobaric incremental elastic modulus, determined by both stiffness of
wall components and vessel geometry, was similar in adult WKY and SHR
vessels. The slope of the incremental elastic modulus versus stress in
vessels from irbesartan-treated SHR was not significantly different
from that in WKY vessels, in contrast to that in untreated SHR vessels
(Table 2).
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Collagen and, therefore, the collagen/elastin ratio were increased in
arteries from adult SHR, but these values were normalized after
irbesartan and fosinopril administration (Table 2).125I-Echistatin binding revealed bands
of 220 and 180 kDa (Figure 5a) in
young and adult SHR and WKY rats that were resistant to
denaturation by SDS.17 These bands were identified by
Western blot as vß3
(180-kDa) and 5ß1
(220-kDa) integrins (Figure 5b). In mesenteric arteries of young
SHR, 5ß1 integrin
levels were lower, whereas
vß3 integrin levels
were similar to those in WKY arteries (Figure 6a). In adult SHR,
vß3 integrins were
overexpressed in mesenteric arteries without changes in
5ß1 integrin levels
(Figure 6b). When normalized to basal levels of age-matched WKY
rats, vß3 and
5ß1 integrin levels
increased with age in SHR. Fosinopril and irbesartan treatment
attenuated age-dependent changes in integrin profile (Figure 6c).
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P<0.01 vs untreated SHR arteries. c, Difference in
percentage between SHR (6 and 20 weeks old) and age-matched WKY rats.
IRBE indicates irbesartan; and FOS, fosinopril. *P<0.05
vs 6-week-old SHR. |
Discussion |
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Mesenteric resistance arteries differ structurally and mechanically between young and adult SHR; these differences are also accompanied by variations in adhesion receptors and media components. At 6 weeks, SHR arteries exhibited eutrophic remodeling and normal stiffness. By 20 weeks, these vessels additionally exhibited growth and stiffening of wall components. Stiffening of adult SHR vessels was associated with increased collagen/elastin ratios and age-related upregulation of
5ß1
and vß3 integrins.
Antihypertensive therapy partially reverted vascular growth, whereas
only irbesartan had a reducing effect on wall stiffness. Fosinopril and
irbesartan lowered but did not normalize SBP, confirming that in SHR,
vascular remodeling is related to the extent of blood pressure
elevation.18 Vascular remodeling in hypertension involves 2 processes. In eutrophic remodeling, wall material appears rearranged around a reduced lumen without evidence of net growth. In hypertrophic remodeling, the media cross section is increased and encroaches on the lumen, indicating the presence of growth.3 As indicated by the growth index of 24%, vascular growth occurred in untreated 20-week-old SHR. The remodeling index of 88% may indicate eutrophic remodeling but is probably partially due to mechanical alterations, since wall components were stiffer in adult SHR.3
The interplay between structure and mechanics of resistance arteries from adult SHR is complicated. The thickened media, by lowering wall stress induced by high pressure, counters late-stage rigidity of wall components so that isobaric stiffness (resulting from wall components and vessel geometry) is not reduced in SHR. This is consistent with previous results obtained also in mesenteric resistance10 and carotid19 arteries. At 20 weeks of age, despite significant stiffening of wall components, geometric adaptation has occurred in SHR to maintain normal in vivo wall stress and stiffness, protecting the vessel wall from pressure-induced damage. In our initial report,10 isobaric stiffness of mesenteric arteries was also normal in adult SHR, but in that study, stiffness of wall components was lower, perhaps because of differences between groups of SHR. The important common finding is strict regulation of isobaric arterial stiffness in SHR, whether by modulating geometry or stiffness of wall components.
Stiffening of wall components in SHR agrees with our recent finding that collagen/elastin ratios are increased in 20-week-old SHR mesenteric small arteries versus WKY arteries,15 also confirmed here. Just as increases in elastin may have diminished stiffness of SHR-SP pial arterioles,6 increased collagen and, therefore, collagen recruitment at lower strain may increase stiffness of SHR mesenteric small arteries. Modifying media composition is not the sole mechanism involved in resistance artery stiffening in SHR. Irbesartan and fosinopril normalized the collagen/elastin ratio in SHR arteries, but only irbesartan reduced arterial stiffness. Also, in human subcutaneous resistance arteries, despite increased collagen/elastin ratios, wall stiffness was lower in vessels from mildly hypertensive patients.20
Changes in RGD-binding integrins that mediate adhesion of cells
to the extracellular matrix may contribute to arterial
remodeling and stiffness of the vascular wall. Integrins are abnormal
in SHR, with a decrease in
5ß1 integrins in young
SHR arteries and an increase in
vß3 integrins in adult
SHR. Increasing cell-matrix attachment sites, perhaps via fibronectin
and 5 integrins, may participate in mechanical
adaptation of aortas in SHR,8 where connections between
smooth muscle cells and elastic lamellas are numerous.21
vß3 and
5ß1 integrins
increased significantly in mesenteric arteries of SHR from 6 to 20
weeks of age. This may represent an increase in cell-matrix
attachment sites intended to modulate arterial structure
and mechanics in hypertension. However, as with collagen, irbesartan
and fosinopril corrected integrin abnormalities in adult SHR arteries,
but only irbesartan reduced arterial stiffness. Thus,
neither wall composition nor integrin profile is the sole determinant
of arterial stiffness. Perhaps topographical distribution
(clustering?) of integrin-mediated attachment sites between
extracellular matrix and vascular smooth muscle cells determines
vascular stiffness in hypertension.
Likewise, expression levels of integrins are not sole determinants of
eutrophic remodeling. Normalization of integrins by irbesartan and
fosinopril was not paralleled by regression of remodeling, again
suggesting that topographical distribution of attachment sites may be
important. However, altered integrin status may be related to the
growth component, because both irbesartan and fosinopril produced
hypotrophic remodeling. Aside from acting as a physical joint,
vß3 integrins may
promote growth functionally. Interactions between
vß3 integrins and
tenascin-C (an extracellular matrix glycoprotein that is
prominent in remodeling tissues) promote epidermal growth
factor–dependent growth and survival of rat pulmonary artery
smooth muscle cells.22 Because tenascin-C induction was
also accelerated in SHR aortas,23 tenascin-C and/or other
vß3 integrin ligands
may protect smooth muscle cells from apoptosis and promote
proliferation and subsequent extracellular matrix deposition.
Vascular remodeling is preventable by early treatment with angiotensin-converting enzyme inhibitors24 25 26 27 and AT1-receptor antagonists.27 28 Losartan also improved vascular structure when administered late to SHR.29 In the present study, with mild blood pressure reduction (from 26 to 35 mm Hg), interrupting the renin-angiotensin system with irbesartan and fosinopril blunted small artery growth with growth indices of -29% and -35%, respectively, relative to untreated SHR. There was little effect on eutrophic remodeling.
Neither irbesartan nor fosinopril normalized blood pressure or
remodeling completely. Vascular remodeling in SHR lowered wall stress
(Figure 3), protecting the vessel from residually elevated blood
pressure. If, in addition to preventing growth, irbesartan and
fosinopril had reversed remodeling, high pressures would have increased
wall stress significantly, predisposing the vascular wall to further
damage. The remodeled lumen reduced circumferential wall tension and
media stress, thereby acting protectively in the face of persistently
high blood pressure after correction of the growth component.
In conclusion, SHR exhibit eutrophic remodeling of mesenteric
resistance arteries by 6 weeks of age, and by 20 weeks, a combination
of vascular growth and remodeling is seen. Interrupting the
renin-angiotensin system interfered with growth but not
eutrophic remodeling of resistance arteries in 20-week-old SHR. Whereas
arterial stiffness was normal in young SHR, with aging to
20 weeks, components of the arterial wall became stiffer.
In adult SHR, differences in lumen diameter may result from a
combination of increased stiffness and eutrophic remodeling. A critical
finding here is that the arterial wall adapts geometrically
to tightly maintain physiologically relevant
pressure-buffering capacity (ie, distensibility and isobaric stiffness)
despite the presence of stiffer components in the vessel wall.
AT1-receptor blockade improved resistance artery
wall stiffness. An increase in the proportion of less distensible
(collagen) to more distensible (elastin) components in adult SHR,
accompanied by an age-related increase in
vß3 and
5ß1 integrins, may
contribute to remodeling and stiffening of resistance arteries in this
genetic model of hypertension.
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Acknowledgments |
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This study was supported by grants from the Medical Research Council of Canada to the Multidisciplinary Research Group on Hypertension, from the Fondation des Maladies du Coeur du Quebec, and from Bristol-Myers Squibb (Princeton, NJ). Dr Intengan is supported by a fellowship from the Medical Research Council of Canada. The authors are grateful to André Turgeon and Geneviève Lapalme for technical assistance.
Received March 12, 1999; revision received July 9, 1999; accepted July 13, 1999.
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