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(Hypertension. 1996;27:159-167.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Increased Pulse Pressure on Cerebral Arterioles
From the University of Iowa College of Medicine, Department of Pathology, and Cardiovascular Center, Iowa City.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Abstract The goal of this study was to examine the hypothesis that increases in pulse pressure produce hypertrophy of cerebral arterioles, even in the absence of increases in mean pressure. Sprague-Dawley rats underwent creation of an arteriovenous fistula and clipping of one carotid artery at 1 month of age. Rats that underwent exposure of the abdominal aorta without fistula production and unilateral carotid clipping served as controls. At about 6 months of age, the mechanics of sham and clipped pial arterioles were examined in vivo in anesthetized rats. Stress-strain relations were calculated from measurements of pial arteriolar pressure (servo null) and diameter and cross-sectional area of the arteriolar wall. Point counting stereology was used to quantify individual components in the arteriolar wall. Before deactivation of smooth muscle with EDTA, cross-sectional areas of the vessel wall and pulse pressures in sham pial arterioles were significantly greater (P<.05) in arteriovenous fistula rats than in control rats (cross-sectional area, 1468±100 versus 1129±104 µm2; pulse pressure, 26±1 versus 14±1 mm Hg). In contrast, systolic and mean pressures in sham arterioles were not significantly different and diastolic pressure was significantly less in arteriovenous fistula rats (systolic pressure, 69±1 versus 67±4 mm Hg; mean pressure, 52±2 versus 57±3 mm Hg; diastolic pressure, 43±2 versus 53±3 mm Hg). Carotid clipping normalized cross-sectional area of the vessel wall (1083±86 µm2) and pulse pressure (12±1 mm Hg) in pial arterioles of arteriovenous fistula rats. During maximal dilatation, the stress-strain curve in sham arterioles of arteriovenous fistula rats was shifted to the right of the curve in control rats, which indicates that arteriovenous fistulae increase passive distensibility of cerebral arterioles. The proportion of distensible components in the vessel wall (smooth muscle, elastin, and endothelium) was increased in sham arterioles of arteriovenous fistula rats. These findings (1) suggest that increases in pulse pressure, even in the absence of increases in mean pressure, are sufficient to produce hypertrophy of cerebral arterioles and (2) provide support for the concept that increases in distensibility of cerebral arterioles in association with hypertrophy of the vessel wall may be related to alterations in wall composition.
Key Words: pulse • cerebral arterioles • hypertrophy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Development of vascular hypertrophy during chronic hypertension has been linked to a variety of determinants. We and others have observed, for example, that sympathetic nerves contribute to hypertrophy of cerebral arterioles in SHRSP1 2 and mesenteric arterioles in SHR.3 In addition to neural stimuli, other determinants that may contribute to hypertrophy include intravascular pressure,4 5 humoral agents,6 7 8 9 and genetic factors.10 11
Of the various determinants that contribute to vascular hypertrophy, it seems reasonable to assume that pressure per se would play an especially important role. Evidence for arterial mean pressure as a determinant of hypertrophy, however, has not always been clear, particularly with respect to small arteries and arterioles. On the other hand, there is increasing evidence that pulse pressure may be an important determinant of vascular hypertrophy. For example, whereas either hydralazine or cilazapril, an ACE inhibitor, prevents hypertrophy and normalizes pulse pressure in cerebral arterioles of SHRSP, only cilazapril normalizes mean pressure.12 These findings cannot be interpreted unambiguously, however, because many antihypertensive treatments have nonpressor effects, such as influences on neurohumoral factors, that may also alter mechanics and structure of blood vessels.
Recently, we examined effects of unilateral carotid clipping on cerebral arterioles of normotensive WKY rats and SHRSP.13 The advantage of unilateral carotid clipping is that neurohumoral factors were the same for cerebral vessels ipsilateral to the carotid clip as for vessels of similar size in the contralateral cerebral hemisphere. Carotid clipping completely prevented hypertrophy of pial arterioles in SHRSP, even though clipping did not normalize mean pressure in pial arterioles of SHRSP with respect to WKY rats. In contrast, PAPPLS was completely normalized by clipping.13 On the basis of these findings, we suggested that pulse pressure may play an important role in the development of cerebrovascular hypertrophy during chronic hypertension. The findings do not, however, completely rule out a role for mean pressure. It is possible that prevention of hypertrophy in cerebral arterioles of SHRSP by carotid clipping requires only that mean pressure is lowered below a critical threshold that is lower than mean pressures normally found in pial arterioles of SHRSP but higher than mean pressures normally found in pial arterioles of WKY rats.
The first goal of this study was to test the hypothesis that increases in pulse pressure, even in the absence of increases in mean pressure, produce hypertrophy of cerebral arterioles. We examined effects of increases in pulse pressure in pial arterioles by creation of an aortocaval AV fistula. It has been shown previously that aortocaval fistulae in Sprague-Dawley rats increase pulse pressure in carotid arteries without increasing mean pressure.14 15 To address the concern that AV fistulae may activate other trophic factors in addition to pulse pressure, such as neurohumoral factors, a clip was placed on one carotid artery to lower intravascular pressure in pial arterioles of one cerebral hemisphere while the same conditions were maintained in both hemispheres with respect to neural and humoral regulation of cerebral blood vessels. The second goal of this study was to examine effects of increased pulse pressure on mechanics and composition of cerebral arterioles. Our hypothesis was that increases in arteriolar pulse pressure might cause a disproportionate increase in vascular muscle and other compliant components of cerebral arterioles and thus lead to an increase in arteriolar distensibility.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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We studied Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, Ind) that had undergone creation of AV fistulae and placement of unilateral carotid clips at 1 month of age. Another group that had undergone exposure of the abdominal aorta without production of an AV fistula and unilateral carotid clipping served as controls. Procedures followed in this study were in accordance with the institutional guidelines set forth by the University of Iowa.
AV fistulae were created in rats by the technique described by Mickle et al.14 After induction of anesthesia with sodium pentobarbital (25 mg·kg body wt-1 IP), the abdominal aorta and inferior vena cava were isolated at the level of the right iliolumbar vein through an incision in the right flank. After the aorta and vena cava were cross-clamped proximal and distal to their bifurcation, a venotomy was performed through the right lateral aspect of the vena cava. The aorta then was penetrated transcavally with a 25-gauge needle, and the transcaval opening was enlarged with microscissors to 1.0 mm in diameter. We chose a 1.0-mm opening because Glassford et al15 showed that a 1.0-mm fistula between abdominal aorta and vena cava results in a large increase in pulse pressure without altering mean arterial pressure in the carotid artery. After irrigation of the opened aorta and vena cava to remove thrombogenic material, the venotomy was closed with 10-0 nylon suture and the flank incision was reapproximated with absorbable suture.
Unilateral carotid clipping was done by a method that we have described previously.13 Clips were made from 2-mm strips of silver sheet with a gap size of 0.30 mm and were placed on the left common carotid artery. The right carotid artery was exposed but not clipped. Because we could not exclude damage to sympathetic nerves by the carotid clip, the superior cervical ganglia were removed on both sides. All rats had ptosis bilaterally.
About 5 months after creation of AV fistulae and placement of carotid clips, we examined mechanics and composition of pial arterioles. Animals were anesthetized with pentobarbital sodium (50 mg·kg body wt-1 IP) and mechanically ventilated with room air supplemented with O2. Paralysis of skeletal muscle was obtained with gallamine triethiodide (20 mg·kg-1 IV). Because the animals were paralyzed, we evaluated them frequently for adequacy of anesthesia. Additional anesthesia was administered when pressure to a paw evoked a change in blood pressure or heart rate.
A catheter was inserted into a femoral vein for infusion of drugs and fluids. A catheter with a pressure transducer embedded in the tip (model SPR-407, Millar Instruments, Inc) was inserted into a femoral artery to record systemic arterial pressure. A catheter was inserted into the other femoral artery to obtain blood samples and withdraw blood to produce hypotension.
Measurement of Pial Arteriolar Pressure and Diameter
Pressure
and diameter were measured in first-order pial
arterioles16 from both the right (sham) and left (clipped)
cerebral hemispheres by use of an open-skull preparation that we
described in detail previously.17 18 We showed
previously
that first-order pial arterioles in WKY rats and SHRSP correspond
to the arteriolar segment immediately distal to the fourth-order
branching point of the middle cerebral artery.17 After
placing the animal in a head holder, we exposed the skull through a
1-cm incision in the skin, retracted the skin edges with sutures, and
placed ports for inflow and outflow of artificial CSF. A dam of dental
acrylic was constructed along the exposed portion of the superior
sagittal suture. Craniotomies were made over the parietal cortex of the
left and right cerebral hemispheres with an air-cooled dental
drill. The dura was incised to expose pial vessels. The
craniotomy over the exposed cerebrum was suffused
continuously with artificial CSF, warmed to 37°C, and equilibrated
with a gas mixture of 5% CO2/95% N2.
The composition of the CSF (in mmol/L) was KCl 3.0, MgCl2
0.6, CaCl2 1.5, NaCl 131.9, NaHCO3 24.6, urea
6.7, and dextrose 3.7. The CSF sampled from the
craniotomy had a pH of 7.24±0.02 (mean±SEM),
PCO2 of 46±3 mm Hg, and
PO2 of 61±2 mm Hg.
Mean, systolic (PAPS), and diastolic (PAPD) pressures and dP/dt were measured continuously in pial arterioles with a micropipette coupled to a servo null pressure measuring system. PAPPLS was calculated as PAPPLS=PAPS-PAPD. The frequency response of the servo null unit (model 4A, Instruments for Physiology and Medicine, Inc) is 0 to 30 Hz. Pipettes were sharpened to a beveled tip of 2 to 4 µm, filled with 1.5 mol/L NaCl, and inserted into the lumen of a pial arteriole with a micromanipulator.
Pial vessels were monitored through a Leitz microscope (NPI x10 objective) connected to a closed-circuit video system with a final magnification of x354. Video images of pial arterioles were digitized with a videocapture board (QuickImage 24, Mass Microsystems) installed in a Macintosh computer (Quadra 900, Apple Computer). Pial arteriolar diameter was measured from the digitized images with image analysis software (NIH Image). The precision of this system is 0.4 to 0.6 µm.
Experimental Protocol
Approximately 30 minutes after
completion of surgery,
systolic, diastolic, and mean pressures, dP/dt, and
diameter were measured in pial arterioles in the right and left
cerebral hemispheres at prevailing levels of systemic
arterial pressure. Vascular smooth muscle of pial
arterioles then was deactivated with EDTA in the suffusate
(67 mmol/L). We showed previously that this concentration of EDTA
produces maximal dilatation of cerebral arterioles in both WKY rats and
SHRSP.17
Pressure-diameter relations were obtained in
deactivated pial arterioles from the sham and clipped
cerebral hemispheres. Arterial blood was withdrawn from a
femoral artery to reduce PAP (in steps of 10 mm Hg) from 70 to 10 mm
Hg. Pial arteriolar diameter stabilized within 15 seconds, and inner
diameter was measured 35 to 45 seconds later. After pressure was
reduced to 10 mm Hg, blood was reinfused to restore pressure to
baseline. The pressure steps then were repeated in the other cerebral
hemisphere. The order in which we studied the sham and clipped
hemispheres was alternated in consecutive experiments. On completion of
the final pressure step, the maximally dilated arterioles were fixed in
vivo by suffusion of arterioles with glutaraldehyde
fixative (0.0225 glutaraldehyde in 0.10 mol/L
cacodylate buffer), while PAP was maintained at 
70 mm Hg.
After the animal was killed, the arteriolar segments used for measurements of pressure and diameter were removed with a microsurgical knife. Fixed arterioles were postfixed in osmium tetroxide (0.01 solution), dehydrated, stained en bloc with uranyl acetate (0.005 solution), and embedded in Spurr's medium. The brain then was removed and examined grossly for evidence of cerebral hemorrhage and infarction. No evidence of hemorrhage or infarction was found in any of the animals examined.
Calculation of Mechanical Characteristics
Incremental
distensibility was calculated from PADi
and PAP: Incremental
Distensibility=
PADi/(PADixPAP)x100,
where PADi is the change in PADi for each
change of PAP (PAP). The units of incremental distensibility are
percent change in pial arteriolar diameter per mm Hg change in PAP
(%/mm Hg). Values of incremental distensibility for each step in PAP
were plotted at the midpoint of the initial and final values of
pressure for each step.
Circumferential strain (
) was estimated as
=(PADi-PADo)/PADo.
Original diameter is defined as diameter at 0 mm Hg or very low
pressure with the vessel extended to in situ
length.19 20
Because blood flow stops during reduction of pressure to 0 mm Hg and
because passive vascular collapse is likely at 0 mm Hg, reliable
measurements of PADi could not be obtained at 0 mm Hg.
Blood flow through pial arterioles at 10 mm Hg of PAP was adequate to
maintain an intact red cell column. Therefore, we calculated strain
using diameter measured at 10 mm Hg.
Circumferential stress (
)
was calculated from PAP,
PADi, and WT: =(PAPxPADi)/(2WT). PAP
was converted from millimeters of mercury to newtons per square meter
(1 mm Hg=1.334x102
N · m-2). On the assumptions that (1)
volume of the vessel wall does not change with changes in vessel
diameter and pressure20 21 and (2) changes in vessel
length during reductions in pressure are small and do not significantly
affect calculations of WT and circumferential stress, we calculated WT
from CSA of the arteriolar wall and PADi:
WT=[(4xCSA/
+PADi2)1/2-PADi]/2.
Histological determinations of CSA were used in all
calculations of WT and circumferential stress.
ET was
estimated by fitting the stress-strain data from
each animal to an exponential curve
(y=aebx)
by least-squares analysis:
=oeß,
where o is stress at original diameter and ß is a
constant related to the rate of increase of the stress-strain
curve. ET was calculated at several different values of
stress from the derivative of the exponential curve:
ET=d/d=ßoeß.
Determination of Wall Composition
CSA of the vessel wall was
measured
histologically from 1-µm sections through a light
microscope interfaced with the image analyzing system described above.
Luminal and total (lumen plus vessel wall) CSAs of the arteriole were
measured by tracing the inner and outer edges of the vessel wall,
defined by the luminal surface of the endothelium and
the abluminal surface of the tunica media, respectively. CSA of the
arteriolar wall was calculated by subtracting luminal CSA from total
CSA. To determine whether glutaraldehyde fixation and
subsequent processing for electron microscopy resulted in significant
shrinkage of pial arterioles, we calculated the inner diameter of fixed
pial arterioles from luminal CSA (CSAL):
CSAL=(4xCSA/)1/2. Inner diameters of
fixed
sham and clipped pial arterioles in control rats (84±7 and 78±6
µm;
n=6) and AV fistula rats (89±5 and 92±5 µm;
n=8) were not
significantly different from inner diameters under in vivo conditions
(Table 1
).
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Volume density of smooth muscle, elastin, collagen, basement membrane, and endothelium was quantified from electron micrographs of the vessel wall by a method that we described previously.18 Ultrathin sections of the arteriolar wall were cut on a Reichart Ultracut microtome and stained with phosphotungstic acid (0.0025 solution). Sections were examined with a Hitachi 7000 electron microscope. Electron micrographs were taken at a standard magnification of x9000 and enlarged by a factor of 3 for a final magnification of x27 000. To ensure uniform sampling, the vessel wall was divided into four quadrants of equal size. Two or three electron micrographs were taken randomly in each quadrant for a total of 9 or 10 electron micrographs per section.
A standard point-counting
grid (double square lattice test system
D16)22 was used to count the number of points contained
within profiles of smooth muscle, elastin, collagen, basement membrane,
and endothelium. Volume density (VV) of
each component was calculated from the number of points in each
component (Pa) and the total number of points contained
within the vessel wall (PT):
VV=Pa/PT. The total numbers
of counts per electron micrograph were 438±17 and 356±15 in sham
and
clipped arterioles in control rats, respectively, and 408±15 and
436±15 in sham and clipped arterioles in AV fistula rats. The total
numbers of counts per vessel were 4597±509 and 3631±283 in sham
and
clipped arterioles in control rats and 3855±385 and 4263±392 in
sham
and clipped arterioles in AV fistula rats. To determine the precision
of counting, the SER of mean volume density was calculated
for each component. The SERs for smooth muscle, elastin,
basement membrane, and endothelium were 
0.10. The
SERs for collagen ranged from 0.10 to 0.14. Thus, the
number of points counted achieved a precision (1-SER)
of at least 0.90 for smooth muscle, elastin, basement membrane, and
endothelium. The precision obtained for collagen, which
was the component with the smallest volume density, was between 0.86
and 0.91. CSA of individual wall components (CSAC) was
calculated from VV of each component and total CSA
(CSAT):
CSAC=CSATxVV.
Statistical Analysis
Comparison of relations of
pressure-diameter, incremental
distensibility, stress-strain, and stress–elastic modulus was
performed with a univariate repeated-measures ANOVA.
The sources of variance were groups (sham and clipped pial arterioles),
subjects within groups, and pressure, strain, or stress. Measurements
of baseline pressure and diameter, coefficients of the
stress-strain relationship (o and ß), total CSA,
WT, andVV and CSA of individual components were compared by
a paired t test for comparisons between sham and clipped
pial arterioles and an unpaired t test for comparisons
between control and AV fistula rats.
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Results |
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Vascular Mechanics
Baseline Measurements
CSA of the vessel wall in sham arterioles was greater in AV fistula rats than in control rats (Table 1
). Pulse pressure and
systolic peak dP/dt in sham pial arterioles were significantly
higher in AV fistula rats than in control rats (Table 1). In
contrast,
systolic and mean pressures in sham pial arterioles were not
significantly different in the two groups of rats. Furthermore,
diastolic pressure and diastolic peak dP/dt in
sham arterioles were significantly less in the AV fistula group than in
the control group. Thus, AV fistulae resulted in
hypertrophy and increases in pulse pressure and
systolic peak dP/dt in cerebral arterioles without increasing
systolic or mean pressure.
Carotid clipping reduced CSA of the vessel
wall; systolic,
diastolic, mean, and pulse pressures; and systolic
and diastolic peak dP/dt in pial arterioles in both groups
of rats (Table 1). CSA of the vessel wall; systolic,
diastolic, mean, and pulse pressures; and systolic
and diastolic peak dP/dt in pial arterioles ipsilateral to
the carotid clip were not significantly different in the two groups
(Table 1). Thus, carotid clipping prevented hypertrophy and
reversed increases in PAPPLS and dP/dt in AV fistula
rats.
Mechanical characteristics. Diameters of sham pial
arterioles were not significantly different in control and AV fistula
rats either before or after deactivation of vascular smooth muscle with
EDTA (Table 1). Carotid clipping did not significantly alter
the
diameter of pial arterioles in either group of rats. After deactivation
with EDTA, pressure-diameter curves in sham arterioles were not
significantly different in control rats and AV fistula rats at
pressures between 10 and 70 mm Hg (Fig 1, left).
Incremental distensibility in sham arterioles was significantly greater
in AV fistula rats than in control rats at all pressures between 10 and
70 mm Hg (Fig 1, right).
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Stress-strain curves closely
approximated an exponential curve in
sham arterioles in control and AV fistula rats
(R2[multiple correlation
coefficient]=0.98±0.01 and 0.97±0.02) (Fig
2, left).
The stress-strain curve in AV fistula rats was shifted to the right
of the curve in control rats. ET in sham arterioles
increased linearly with respect to stress in both groups of rats
(Fig 2, right). The slope of ET versus stress in
sham
arterioles was significantly less in AV fistula rats than in control
rats (4.2±0.3 versus 5.6±0.7; P<.05). Carotid
clipping
increased the slope of ET versus stress in AV fistula rats
(4.2±0.3 to 5.6±0.2) but not in control rats (5.6±0.7 and
5.5±0.5;
P>.05). The slope of ET versus stress reflects
stiffness of biological tissue,23 24 so these
findings
suggest that AV fistulae result in reduced stiffness of cerebral
arterioles. The findings also suggest that reductions in stiffness of
cerebral arterioles by AV fistulae are prevented by carotid
clipping.
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Vascular Composition
Most of the hypertrophy that occurred in
sham
arterioles of AV fistula rats resulted from increases in CSAs of smooth
muscle and elastin, whereas CSAs of collagen, basement membrane, and
endothelium did not increase significantly (Table 2). Thus,
hypertrophy of sham arterioles in
AV fistula rats resulted primarily from increases in the more
distensible components of the arteriolar wall, smooth muscle, and
elastin, whereas the stiffer components, collagen and basement
membrane, contributed little to the increase in wall mass.
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CSAs of
smooth muscle and elastin were significantly less in clipped
than in sham arterioles in AV fistula rats but not in control rats
(Table 2). CSAs of collagen, basement membrane, and
endothelium were not significantly different in clipped
and sham arterioles in either group of rats (Table 2). Thus,
carotid
clipping normalized composition of pial arterioles in AV fistula
rats.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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There are two major findings in this study. First, AV fistulae result in increases in pulse pressure but not mean pressure in cerebral arterioles of Sprague-Dawley rats. Increases in pulse pressure are accompanied by hypertrophy of the arteriolar wall. Furthermore, carotid clipping normalizes pulse pressure and prevents hypertrophy in cerebral arterioles of AV fistula rats. These findings suggest that increases in pulse pressure, even in the absence of increases in systolic and mean pressures, are sufficient to produce hypertrophy of cerebral arterioles. Second, distensibility of cerebral arterioles is increased in AV fistula rats, despite hypertrophy of the arteriolar wall. In addition, hypertrophy of cerebral arterioles is associated with a disproportionate increase in distensible components of the arteriolar wall. Furthermore, prevention of hypertrophy by carotid clipping normalizes composition of the arteriolar wall and prevents increases in arteriolar distensibility. These findings provide support for the concept that increases in distensibility of cerebral arterioles that accompany hypertrophy may be related to alterations in composition of the vessel wall.
Consideration of Methods
The goal of AV fistulae was to
increase pulse pressure in cerebral
arterioles without increasing mean arterial pressure. We
used an aortocaval fistula because Glassford et al15 had
shown previously that a 1-mm fistula between abdominal aorta and
inferior vena cava results in a large increase in pulse
pressure without altering mean pressure in the carotid artery. A
potential concern with this approach is that an AV fistula may
activate other trophic factors in addition to pulse pressure,
such as neurohumoral factors. To address this concern, we placed a clip
on one carotid artery to lower intravascular pressure in pial
arterioles of one cerebral hemisphere while maintaining the same
conditions in both hemispheres with respect to neural and humoral
regulation of cerebral blood vessels. Because sympathetic nerves
modulate the structure and mechanics of cerebral arterioles and because
of the close proximity of the internal carotid artery to sympathetic
nerves, we concluded that the carotid clip or fibrosis induced by the
clip might damage sympathetic nerves and, thus, alter mechanics and
structure of pial arterioles independently of reductions in
PAPPLS. To ensure that pial arterioles in both cerebral
hemispheres were exposed to the same level of sympathetic input during
the interval between placement of the carotid clip and examination of
arteriolar mechanics and composition, we removed the superior cervical
ganglia on both sides at the time the clip was placed.
Another consideration with respect to methods is the relatively long period of time between creation of AV fistulae and examination of pial arterioles. Hypertrophy of the left ventricle and aorta occurs within 3 to 9 days after induction of aortic coarctation in rats.25 In this study, the effects of AV fistulae on the structure of pial arterioles were not examined until 5 months after fistulae were created. One might speculate, therefore, that the time between creation of AV fistulae and induction of pial arteriolar hypertrophy may have been substantially less than the time between fistula creation and examination of pial arterioles. If so, one could further speculate that pulse pressure might not have been the controlling variable with respect to induction of pial arteriolar hypertrophy by AV fistulae. We cannot rule out this possibility because the time required to develop pial arteriolar hypertrophy after fistula creation was not determined in this study. On the other hand, it is likely that PAPPLS was increased simultaneously with creation of AV fistulae or shortly thereafter. In that case, it would have been possible for increases in pulse pressure to have contributed to induction as well as maintenance of pial arteriolar hypertrophy in AV fistula rats.
The method we used to examine the mechanics of pial arterioles takes into account several factors that could compromise our calculations of stress, strain, and ET. These factors include plasma skimming, effectiveness of smooth muscle deactivation, compressibility of the vessel wall, effects of intravascular pressure on vessel length, and definition of original diameter in the determination of strain. These factors have been considered in detail previously.17 26
With respect to the application of point-counting methods to cerebral arterioles, we considered three factors that could compromise our estimates of composition of the arteriolar wall. First, the large disparity in volume density of the various components in the pial arteriolar wall requires that the criteria for determining optimal point density22 are closely observed. Second, random sampling of the arteriolar wall may be impeded by heterogeneous distribution of the components within the arteriolar wall. Third, the arachnoid layer adjacent to the outer surface of pial vessels was not included in our calculations of volume density. We considered these factors in detail previously.18
Consideration of Previous Studies
Previous studies of effects
of AV fistulae on vascular structure
focused on large arteries immediately proximal to the fistula.
Observations in patients led to the conclusion that arteries adjacent
to AV fistulae undergo dilatation accompanied by thinning of the vessel
wall, whereas veins undergo arterialization with
hypertrophy of the wall.27 In many of the
patients, the presence of fistulae was known to be of long duration
(>2 years). Experimental studies in dogs suggest that changes in
structure of arteries adjacent to AV fistulae vary with duration of the
fistula.28 CSA of the wall was increased in femoral and
carotid arteries that had been exposed to AV fistulae for periods of up
to 16 months. Arteries exposed to AV fistulae for longer periods (>18
months), on the other hand, resulted in reductions of CSA of the vessel
wall.
In contrast to previous studies, this study apparently is the first to examine the effects of AV fistulae on the structure of arterioles. Our finding that CSA of the vessel wall is increased in pial arterioles of rats with aortocaval fistulae suggests that exposure of small as well as large arteries to the hemodynamic effects of AV fistulae results in hypertrophy of the vessel wall.
Determinants of Hypertrophy
Cerebral arterioles undergo
hypertrophy with a
paradoxical increase in distensibility in SHRSP,17
SHR,26 and rats with one-kidney, one clip renal
hypertension.26 Cerebral arterioles in
SHRSP17 and SHR26 also undergo remodeling of
the vessel wall, with a reduction in external diameter. Thus, chronic
hypertension alters mechanics and structure of cerebral
arterioles.
Vascular hypertrophy during chronic hypertension has been linked to a variety of determinants, including intravascular pressure,4 5 neural factors,1 2 humoral agents,3 6 7 8 9 and genetic factors.10 11 Of the various factors that may contribute to vascular structure, one might assume that arterial pressure per se would play an especially important role. With respect to mean arterial pressure, however, the evidence has not always been completely convincing, particularly with regard to small arteries and arterioles. Although treatment of hypertension has been shown to reverse medial hypertrophy in small arteries and arterioles in several vascular beds including mesentery,29 kidney,30 cerebrum,31 and muscle,32 the degree of reversal often has not matched the degree of reduction in mean arterial pressure.33 34 35
In contrast to mean arterial pressure, there is a growing body of evidence that pulse pressure may play an important role in alterations of vascular structure during hypertension. For example, both hydralazine and cilazapril, an ACE inhibitor, prevent hypertrophy of cerebral arterioles in SHRSP.12 Hydralazine and cilazapril also are equally effective in reducing pulse pressure in cerebral arterioles of SHRSP, even though hydralazine is less effective in reducing mean arterial pressure.12 In another study, Christensen et al36 examined effects of a variety of antihypertensive agents, including an ACE inhibitor, a calcium antagonist, a beta1-blocker, and a vasodilator, on structural characteristics in small mesenteric arteries in SHR. Whereas each of the antihypertensive treatments significantly reduced all parameters of blood pressure in SHR (except for metoprolol, which did not lower pulse pressure), only the ACE inhibitor and the beta1-blocker significantly reduced the media-to-lumen ratio. The correlation between individual parameters of blood pressure and media-to-lumen ratio was stronger for pulse pressure than for systolic blood pressure, mean blood pressure, or diastolic blood pressure. Interpretation of the findings in these studies12 36 is complicated, however, because antihypertensive treatment has nonpressor effects, such as influences on neurohumoral factors, that may also alter mechanics and structure of blood vessels. Findings based on treatment or reversal of hypertension, therefore, do not allow unambiguous separation of effects of intravascular pressure from neurohumoral effects on vascular structure and mechanics.
An approach that avoids some of the disadvantages of antihypertensive treatment is local reduction in pressure by ligation of upstream vessels. Using this approach, we found previously that ligation of the internal carotid artery prevents hypertrophy and normalizes pulse pressure but not systolic pressure and mean pressure in pial arterioles of SHRSP.13 Furthermore, there was not a significant correlation between CSA of the vessel wall and systolic pressure or mean pressure in sham and clipped pial arterioles of WKY rats and SHRSP.13 There was, on the other hand, a strong correlation between CSA and pulse pressure.13 Although these findings provide support for the concept that pulse pressure is an important determinant of cerebral vascular hypertrophy during hypertension, another consideration remained. Hypertrophy of pial arterioles may not occur until PAP is increased above a critical threshold that is lower than pressures normally found in pial arterioles of SHRSP but higher than pressures normally found in pial arterioles of WKY rats. Thus, even though pial arteriolar systolic, diastolic, and mean pressures were not normalized by carotid clipping in SHRSP, these parameters may have been reduced sufficiently to prevent hypertrophy of pial arterioles in SHRSP.
The present study addresses this possibility and extends the concept that pulse pressure may be a determinant of vascular growth. We demonstrated that AV fistulae result in hypertrophy and increases in pulse pressure but not mean pressure in cerebral arterioles of Sprague-Dawley rats. Furthermore, increases in PAPPLS in AV fistula rats resulted almost entirely from reductions in the diastolic component of PAP. The systolic component of PAP was not significantly altered by AV fistulae. In addition, both hypertrophy and increases in pulse pressure were prevented in cerebral arterioles of AV fistula rats by carotid clipping. These findings suggest that increases in pulse pressure, even in the absence of increases in systolic and mean pressures, are sufficient to produce hypertrophy of cerebral arterioles.
Another factor that may have contributed to hypertrophy of pial arterioles in AV fistula rats was dP/dt. This possibility is suggested by the finding that AV fistulae produced increases in both systolic and diastolic peak dP/dt in pial arterioles. We think this possibility is unlikely, however, on the basis of our previous finding that hypertrophy of pial arterioles in SHRSP13 17 is not accompanied by an increase in either systolic or diastolic peak dP/dt.37
We also considered the possibility that increases in shear stress may play a role in the production of vascular hypertrophy by AV fistulae, because shear stress influences production of growth factors in vascular endothelium, such as PDGF,38 39 40 41 endothelin,42 43 and nitric oxide.44 45 46 However, we believe that it is unlikely that increases in shear stress play a role in hypertrophy of pial arterioles of the AV fistula rats that were examined in this study. The rationale for this statement is that, whereas shear stress would be expected to be significantly increased in large arteries proximal and distal to the fistula, one would not necessarily expect shear stress to be increased in arterioles that are remote from the fistula site.
Distensibility and Composition
In previous studies, we found
that distensibility of fully relaxed
cerebral arterioles is increased paradoxically in SHRSP, SHR, and rats
with one-kidney, one clip renal hypertension, despite
hypertrophy of the arteriolar wall.17 26 This
study indicates that hypertrophy in normotensive rats with
AV fistulae, as well as in hypertensive rats, is accompanied by an
increase in distensibility of cerebral arterioles. Thus,
hypertrophy of cerebral arterioles results in increased
distensibility of the arteriolar wall, even in the absence of
hypertension.
We proposed previously that increases in passive distensibility that accompany hypertrophy of cerebral arterioles may be due to alterations in proportional composition of the arteriolar wall.2 13 18 26 The findings in this study provide additional support for this concept. To relate alterations in structure of pial arterioles to alterations in distensibility, we calculated the ratio of nondistensible to distensible components in the arteriolar wall, as discussed previously.2 18 Basement membrane was included with the relatively nondistensible element, collagen, because basement membrane contains significant amounts of type IV collagen.47 48 Smooth muscle, on the other hand, was included with the relatively distensible elements because its elastic modulus is similar to that of elastin.49 Endothelium was included with the distensible elements because its elastic modulus is assumed to be equal to or less than the elastic modulus of smooth muscle.23
When basement membrane (BSM) was combined with collagen (C) and smooth muscle (SM) and endothelium (Endo) were combined with elastin (E), the ratio of nondistensible to distensible components ([C+BSM]/[E+SM+Endo]) in sham pial arterioles was less in AV fistula rats than in control rats (0.10±0.009 versus 0.14±0.011; P<.05). Thus, when all of the major components of the arteriolar wall are taken into account, hypertrophy of pial arterioles in rats with AV fistulae is accompanied by a relative increase in the more compliant components of the arteriolar wall. These findings, together with findings from our previous studies,17 18 suggest that chronic hypertension may produce alterations in proportional composition of cerebral arterioles which, in turn, contribute to increases in arteriolar distensibility.
The association of alterations in composition and mechanics of cerebral vessels, however, may be coincidental and therefore must be interpreted with caution. The relation of vascular structure and distensibility is complex and undoubtedly depends on factors in addition to proportional composition, including orientation of wall components with respect to vascular circumference and interconnections among the various components.50 In some vessels, alterations in composition may not be predictive of alterations in vascular mechanics. For example, distensibility of the internal carotid artery is decreased in SHR, despite a reduction in the ratio of collagen to elastin.51
Implications
The findings in this study suggest that
increases in pulse
pressure, even when not accompanied by increases in mean pressure, may
be sufficient to produce hypertrophy of cerebral
arterioles. Pulse pressure is a dynamic component of
arterial pressure. In contrast, mean pressure is a static
component. An implication of these findings, therefore, is that the
relation between cerebral vascular hypertrophy may depend
to a greater extent on dynamic or time-dependent than on static or
steady state–dependent components of arterial
pressure.
Support for this concept is provided by studies of vascular cells in tissue culture. In vascular smooth muscle that is grown in culture, DNA synthesis and rate of growth are greater in cells that are subjected to cyclic stretching than in cells that are grown under static conditions.52 53 In addition, cyclic strain results in increased secretion of PDGF by vascular smooth muscle cells.54 Furthermore, treatment of vascular smooth muscle with antibodies to PDGF suppresses increases in DNA synthesis produced by cyclic strain.54 Cyclic strain also enhances the mitogenic activity of angiotensin II on rat vascular smooth muscle cells, an effect that is blocked by pretreatment of cells with antibodies to PDGF.55 These findings suggest that the trophic action of cyclic strain may be mediated by strain-induced production of PDGF. In addition to stimulation and modulation of cell growth, cyclic strain also plays a role in cell orientation.56 57 Under static conditions, vascular smooth muscle cells in tissue culture assume a random orientation. When exposed to cyclic strain, vascular smooth muscle cells realign in a direction perpendicular to the direction of strain, an effect that is preceded and perhaps guided by reorganization and reorientation of intracellular actin filaments.57
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by funds from the Iowa Affiliate of the American Heart Association and grants HL-22149 and NS-24621 from the National Institutes of Health. Dr Baumbach is the recipient of an Established Investigatorship Award from the American Heart Association. We thank Shams Ghoneim and Ronald McElmurry for technical assistance and Dr Donald Heistad for critical review of the manuscript.
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Footnotes |
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Reprint requests to Gary L. Baumbach, MD, Department of Pathology, 147 Medical Laboratories, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail g-baumbach@uiowa.edu.
Received August 2, 1995; first decision August 29, 1995; accepted November 14, 1995.
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References |
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