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© 1997 American Heart Association, Inc.
Articles |
Comparison of Aorta and Pulmonary Artery
I. Early Cholesterol Accumulation and Relative Susceptibility to Atheromatous Lesions
From the Department of Pathology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.
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Abstract |
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Abstract In rabbits, the pulmonary artery and the aorta are susceptible to atherosclerosis. However, susceptibility of the pulmonary artery, compared with the aortic arch, to atherosclerosis and the relationship between the accumulation of cholesterol during the early stages of atherogenesis and the development of atheromatous lesions for these arterial regions remain to be clarified. Cholesterol concentrations for the pulmonary artery and aorta were measured in normal rabbits and in rabbits fed a 0.5% cholesterol diet for 8, 12, and 16 days and 17 weeks. In normal rabbits, the rank order of arterial cholesterol concentrations was pulmonary artery>aortic arch>descending thoracic aorta, with concentrations of total and nonesterified cholesterol 17% and 25% (both P<.05) greater, respectively, for the pulmonary artery than for the descending thoracic aorta. Rank order remained the same during 16 days of cholesterol feeding, but differences between arterial regions were exaggerated. After rabbits were fed cholesterol for 16 days, total and esterified cholesterol concentrations were 57% and 920% (both P<.01) greater, respectively, for the pulmonary artery than for the descending thoracic aorta, with much smaller differences between the aortic regions. In contrast, after rabbits were fed cholesterol for 17 weeks, concentrations of total, esterified, and nonesterified cholesterol were similar for the pulmonary artery and aortic arch, but these forms of cholesterol were increased 100%, 130%, and 53% (all P<.03), respectively, for the aortic arch compared with the descending thoracic aorta. Cholesterol concentrations for the pulmonary artery were positively associated with those for the aortic regions during the first 16 days of cholesterol feeding, but for rabbits fed cholesterol for 17 weeks the associations were either negative or absent. These results indicate that relative rates of cholesterol accumulation in the pulmonary artery and aorta differ at different stages of atherogenesis and suggest that the balance between processes that deliver cholesterol to, and remove cholesterol from, the artery may change in different ways in these arterial regions during atherogenesis.
Key Words: aorta • atherosclerosis • atherosclerosis susceptibility • cholesterol • pulmonary artery
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rabbits with dietary-induced1 2 3 4 5 6 7 8 9 and spontaneous hypercholesterolemia10 11 12 develop atherosclerotic lesions in the pulmonary artery. If hemodynamics play a role in atherosclerosis, as data suggest,13 14 15 16 the much lower blood pressure in the pulmonary artery than in the aorta17 would suggest that the pulmonary artery would be less susceptible to atherosclerosis than the aorta. However, the pulmonary artery and aortic arch (the part of the aorta with similar proximity to the heart as the pulmonary artery) also differ in structure, thickness, and cellularity17 18 ; it is not clear how this combination of factors would influence atherosclerosis. Some studies in rabbits fed cholesterol reported that pulmonary artery atherosclerosis was less extensive than aortic atherosclerosis,3 5 8 19 whereas another study suggested that pulmonary atherosclerosis was at least as extensive as aortic atherosclerosis.6 Although susceptibility to atherosclerosis within the aorta decreases with increasing distance from the heart,6 11 12 20 21 22 23 only two studies involving relatively few rabbits1 6 compared atherosclerosis in the pulmonary artery with that in the aortic arch. These studies suggest that pulmonary atherosclerosis was at least as severe as that in the aortic arch.1 6
We reported that focal atherosclerosis-susceptible areas within the aorta accumulate cholesterol more rapidly during short intervals of cholesterol feeding than do the surrounding atherosclerosis-resistant aortic regions.24 However, there are little if any quantitative data in the literature concerning the early stages of atherosclerosis in the pulmonary artery compared with the aorta and for the entire descending thoracic and arch regions of the thoracic aorta. In addition, a study that considered different intervals of dietary treatment reported inconsistent results for differences between atherosclerosis in the pulmonary artery and the aorta as a whole.4 Thus, atherogenesis in the pulmonary artery and different aortic regions remains to be clarified.
One aim of the present study was to characterize cholesterol accumulation in the aortic arch and pulmonary artery of normal rabbits and in rabbits after short intervals of cholesterol feeding. The descending thoracic aorta was also studied as a reference aortic region that is less susceptible to atherosclerosis than is the aortic arch.6 11 12 20 21 22 23 The second aim of the present study was to assess the relative susceptibility of the aortic arch and pulmonary artery to atherosclerosis. Finally, we sought to determine whether arterial cholesterol accumulation after short intervals of cholesterol feeding would accurately predict relative susceptibility to atherosclerosis for the pulmonary artery, aortic arch, and descending thoracic aorta.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rabbits
These studies used sexually mature young female New Zealand White rabbits. Short-term arterial cholesterol accumulation was studied in 43 rabbits (33 rabbits from Franklin's Rabbitry and Supply, Wake Forest, NC, and 10 rabbits from Robinson Services, Inc, Winston-Salem, NC). The source of rabbits did not influence arterial cholesterol. Development of atheromatous lesions was studied in 8 rabbits from Robinson Services, Inc. After acclimation to the animal facilities24 and before entering the studies, rabbits weighed
2.5 kg. Rabbits weighed 2.60±0.04 kg (mean±SEM, n=42) at
the end of the study of short-term cholesterol accumulation
and 3.28±0.07 kg (n=8) at the end of the study of
atheromatous lesion formation. Rabbits were studied
while they consumed either cholesterol-free rabbit chow
(Prolab) or the same diet supplemented with cholesterol and
2.5% corn oil. The cholesterol concentration in the diet
was 0.5%, except as noted in Table 1
.
All rabbits were fed 100 g of their respective diets each day.
Blood samples (1 mL) were collected24 after an overnight
fast while the rabbits were consuming cholesterol-free
rabbit chow. Additional samples were collected every 4 days for rabbits
fed cholesterol for 
16 days and every 2 weeks for rabbits
fed cholesterol for 17 weeks. All blood samples were
collected into 0.01 vol of 0.4 mol/L EDTA.
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Plasma and Lipoprotein Cholesterol Concentrations
Blood samples were collected after an overnight fast from all
rabbits just before they were euthanized to measure plasma and
lipoprotein (only for rabbits fed cholesterol for 17 weeks)
cholesterol concentrations. Lipoproteins (VLDL+IDL, LDL,
and HDL) were isolated by differential
centrifugation25 as d<1.020,
1.020<d<1.060, and d>1.060 g/mL plasma fractions,
respectively. Plasma and lipoprotein cholesterol
concentrations were measured by an enzymatic method.26
Arterial Sampling
Most rabbits were euthanized by an overdose of pentobarbital
sodium (100 mg/kg body wt). A few were exsanguinated after they
were deeply anesthetized with ketamine hydrochloride
and xylazine (60 and 6 mg/kg body wt, respectively). Similar
numbers of untreated rabbits and those fed cholesterol for
8, 12, and 16 days were studied at a given time. The rabbits fed
cholesterol for 17 weeks were studied in a separate
experiment.
The aorta and pulmonary artery trunk were removed with the heart. These arteries were separated from the heart.27 Thoracic and abdominal regions of the aorta were separated.24 After adventitial tissue was removed, the thoracic aorta and pulmonary artery were opened longitudinally and pinned flat.28 29 30 These arterial samples were photographed both before and after separating the aortic arch from the descending thoracic aorta.24 Arterial samples were kept at 4°C whenever possible and were weighed and frozen at -20°C until analysis. Surface areas of arterial samples from rabbits fed cholesterol for 17 weeks were measured.28 29 30 The thickness of atheromatous arteries was calculated by dividing fresh weights of arterial samples by the product of the corresponding arterial surface areas and arterial density. The density of fresh artery was estimated from the density of fixed rabbit artery31 and data for dehydration of rabbit thoracic aorta upon fixation.30
Arterial Cholesterol Concentrations
Lipids were extracted from arterial samples with 2:1
(vol/vol) chloroform/methanol.24 32 For the study
of short-term arterial cholesterol
accumulation, esterified and nonesterified cholesterol in
solvent extracts were separated by thin-layer
chromatography.24 Total
cholesterol (all samples) and nonesterified
cholesterol (most samples) were determined as described
previously.24 33 34 For the study of arterial
cholesterol accumulation in rabbits fed
cholesterol for 17 weeks, both total and nonesterified
cholesterol concentrations were measured in solvent
extracts by enzymatic methods using cholesterol esterase
and cholesterol oxidase and using only
cholesterol oxidase, respectively.35
Esterified cholesterol concentrations in
arterial samples were determined as the difference between
the measured total and nonesterified cholesterol
concentrations. Each cholesterol assay included a solvent
extract of a control sample (level 2, Solomon Park). For the study of
short-term cholesterol accumulation, mean intraassay and
interassay coefficients of variation for this control sample were 3.6%
and 8.3%, respectively. For total and nonesterified
cholesterol measured in arteries of rabbits fed
cholesterol for 17 weeks, intraassay coefficients of
variation were 2.7% and 1.8%, respectively; interassay coefficients
of variation were 1.2% and 1.2%, respectively.
Cholesterol Exposure Index
The arterial exposure to elevated plasma
cholesterol (cholesterol exposure index) was
calculated by determining the area under the curve of the increment in
plasma cholesterol concentration above the normal value
versus time of cholesterol feeding as described
previously.24
Statistical Methods
The three arterial regions were compared by ANOVA
with a multiple-measures design.36 When necessary to
stabilize variances among arterial regions, data were
transformed to logarithms before ANOVA. When the ANOVA was significant,
pairwise comparisons were performed among the three
arterial regions.37 Pairwise comparisons of
arterial regions after different intervals of
cholesterol feeding were performed by ANOVA with multiple
measures for arterial regions and by grouping data
according to the duration of cholesterol
feeding.36 Probability values were adjusted using the
Bonferroni criteria to account for multiple comparisons.38
Other comparisons were performed by the method of
Scheffé.37 Regression analysis was used to
investigate the relationship between arterial
cholesterol concentrations and both duration of
cholesterol feeding and cholesterol exposure
index.24 37 Correlations between cholesterol
concentrations in different arterial regions were also
determined.37 A value of P<.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cholesterol Concentrations for Arterial Regions of Normal Rabbits
For normal rabbits, the rank order for total and nonesterified cholesterol was pulmonary artery>aortic arch>descending thoracic aorta (Table 2
). Most of the differences among
arterial regions were due to higher values for the
pulmonary artery.
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Changes in Arterial Cholesterol
Concentrations During the First 16 Days of Cholesterol Feeding
Total cholesterol concentrations increased
for the pulmonary artery and aortic arch. Esterified
cholesterol concentrations increased only for the
pulmonary artery; nonesterified cholesterol
concentrations increased for all arterial regions
(Table 2
). Throughout the 16-day period of cholesterol
feeding, the rank order for total and nonesterified
cholesterol remained pulmonary artery>aortic
arch>descending thoracic aorta, but differences among arterial regions
were exaggerated. For the entire 16 days of cholesterol feeding
considered as a whole, concentrations of total, esterified, and
nonesterified cholesterol were consistently higher
for the pulmonary artery compared with the aortic regions.
Interestingly, the percentage of cholesterol esterified was
consistently higher for the pulmonary artery compared
with the aortic regions.
Morphological Features of Atheromatous Aorta and
Pulmonary Artery
For rabbits fed cholesterol for 17 weeks, the
rank order for atherosclerotic lesion areas and arterial
thickness was aortic arch>pulmonary artery>descending
thoracic aorta (Table 3). Atherosclerotic
lesion areas differed among regions, but no pairwise comparisons were
significant. In contrast, all pairwise comparisons were significant for
arterial thickness.
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Cholesterol in Atheromatous Aorta and
Pulmonary Artery
Whether expressed per unit weight or per unit surface area, the
rank order for total and nonesterified cholesterol was
aortic arch>pulmonary artery
descending thoracic aorta (Table 3). The rank order for esterified cholesterol differed on a
weight basis (pulmonary artery>aortic arch) and on a
surface-area basis (aortic arch>pulmonary artery). The rank
order for percentage of cholesterol esterified was
pulmonary artery>aortic arch>descending thoracic aorta. The
only significant differences between pulmonary artery and
aortic arch were for nonesterified cholesterol per unit
surface area and percentage of cholesterol esterified. In
contrast, all differences between aortic arch and descending thoracic
aorta were significant.
Relationship Between Arterial Cholesterol
and Cholesterol Exposure Index
For normal rabbits and those fed cholesterol for up to
16 days combined, arterial total cholesterol
concentrations were positively associated with the
cholesterol exposure index for the pulmonary artery
and aortic arch (Fig 1, left side, top
and middle panels). Surprisingly, for rabbits fed
cholesterol for 17 weeks, arterial total
cholesterol concentrations were not associated with the
cholesterol exposure index for any arterial
region (Fig 1, right side).
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indicates rabbits
never fed cholesterol (n=12); 
, rabbits fed
cholesterol for 8 days (n=11); 
, rabbits fed
cholesterol for 12 days (n=9); and 
, rabbits fed
cholesterol for 16 days (n=11). Right, Rabbits fed
cholesterol for 17 weeks (n=8). Regression lines were
determined from all the data shown. When the apparent outlier in the
top left panel was excluded, the r value was reduced to .42,
and the P value was .007. The slope of the regression line
was also reduced but was still 68% greater than that for the aortic
arch of the same rabbits.For rabbits fed cholesterol up to 16 days, arterial esterified cholesterol concentrations were also related to the cholesterol exposure index for the pulmonary artery, with a trend for the aortic arch (data not shown). In comparison, for rabbits fed cholesterol for 17 weeks, neither arterial esterified nor nonesterified cholesterol was related to the cholesterol exposure index for any arterial region (data not shown).
Relationship Between the Pulmonary Artery and the Two
Aortic Regions for Cholesterol Accumulation in Rabbits Fed
Cholesterol for up to 16 Days
There was a positive association between the pulmonary
artery and aortic arch for accumulation of total, esterified, and
nonesterified cholesterol (Fig 2, left side). Similar associations were
found between the pulmonary artery and descending thoracic
aorta for accumulation of total and nonesterified
cholesterol (Fig 2, right side).
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Relationship Between Pulmonary Artery and the Aortic
Regions for Cholesterol Accumulation and
Atheromatous Lesions in Rabbits Fed
Cholesterol for 17 Weeks
There was an inverse relationship between pulmonary artery
and aortic arch for accumulation of both total and esterified
cholesterol (Fig 3, left
side). Nonsignificant trends in the same direction were observed
between the pulmonary artery and aortic arch for nonesterified
cholesterol and for associations between the
pulmonary artery and descending thoracic aorta for accumulation
of all forms of cholesterol (Fig 3, right side). Surface
areas of atheromatous lesions in the pulmonary
artery were not related to surface areas of
atheromatous lesions in either the aortic arch (Fig 3, bottom left) or descending thoracic aorta (Fig 3, bottom right).
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Relationship Between Aortic Arch and Descending Thoracic Aorta for
Cholesterol Accumulation and Atheromatous Lesions
For normal rabbits and those fed cholesterol for up to
16 days combined, there was a strong positive association between the
aortic arch and descending thoracic aorta for accumulation of both
total and nonesterified cholesterol (Fig 4, left side). Similar relationships were
present for these forms of cholesterol for rabbits fed
cholesterol for 17 weeks (Fig 4, right side). At this time,
there were also strong positive associations between the aortic arch
and descending thoracic aorta for esterified cholesterol
and for areas of atheromatous lesions (Fig 4, bottom
right). Interestingly, associations between the aortic arch and
descending thoracic aorta for all forms of cholesterol for
rabbits fed cholesterol for 17 weeks were
consistently at least as strong as the corresponding
associations for rabbits fed cholesterol for up to 16 days.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we sought to characterize cholesterol accumulation during early cholesterol feeding and relative susceptibility to atherosclerosis for the pulmonary artery, aortic arch, and descending thoracic aorta. We also investigated whether relative susceptibility of these regions to atherosclerosis was related to the time dependence of cholesterol accumulation during short intervals of cholesterol feeding. In the present study, we report that atheromatous lesion development in rabbits fed cholesterol for 17 weeks was similar for the aortic arch and pulmonary artery, with more extensive atherosclerosis in the aortic arch than in the descending thoracic aorta. These data are consistent with the more rapid cholesterol accumulation in the pulmonary artery and aortic arch than in the descending thoracic aorta during the first 16 days of cholesterol feeding. However, total, esterified, and nonesterified cholesterol concentrations were consistently higher for the pulmonary artery than for the aortic arch during the first 16 days of cholesterol feeding, in contrast to atheromatous lesion development after 17 weeks of cholesterol feeding.
Atherosclerosis in Pulmonary Artery and
Aortic Arch
Data for susceptibility of the pulmonary artery and aortic
arch to atherosclerosis are inconsistent. Some
studies3 4 8 19 found the atherosclerotic lesion area to
be reduced in the pulmonary artery compared with the entire
aorta. Because the atherosclerotic lesion area for the entire aorta is
only 1/4 to 1/2 of that for the aortic arch,6 11 12 22 23
one could infer that those studies found reduced
atherosclerosis in the pulmonary artery
compared with the aortic arch. In contrast, other studies that directly
compared atherosclerosis in the pulmonary
artery and aortic arch found the atherosclerotic lesion
area6 and arterial cholesterol
concentrations1 to be at least as great for the
pulmonary artery as for the aortic arch and greater than for
the descending thoracic aorta. Our data agree with the direct
comparisons of atherosclerosis in the pulmonary
artery and aortic arch.
Arterial Esterified Cholesterol
An earlier study in rabbits reported a higher percentage of
cholesterol to be esterified in the pulmonary
artery compared with the aortic arch.1 Our data for 12
days, 16 days, and 17 weeks of cholesterol feeding are
consistent with that report. Most esterified
cholesterol in atherosclerotic lesions is in foam cells,
many of which are derived from macrophages.39 40 41
In contrast, nonesterified cholesterol accumulating
after cholesterol feeding is first found in extracellular
vesicles42 43 44 ; later it appears as cholesterol
clefts.45 46 It is possible that macrophage
recruitment into the pulmonary artery is more efficient than
recruitment into the aortic arch early in cholesterol
feeding and that increased macrophage density persists in the
pulmonary artery during atherogenesis. The higher percentage of
esterified cholesterol in the pulmonary artery
compared with the aortic arch might suggest that either
acylcholesterol:acyltransferase activity was increased or
lysosomal cholesterol hydrolysis was reduced in the
pulmonary artery. Such an imbalance could reduce the pool of
nonesterified cholesterol available for efflux.
Association of Arterial Cholesterol
Accumulation With Plasma Cholesterol
Cholesterol accumulation in the aortas of rabbits fed
cholesterol for several months47 48 49 and that
in atherosclerosis-susceptible aortic sites in rabbits
fed cholesterol for up to 16 days24 is
positively associated with the cholesterol exposure index.
Our data for aortic arch and pulmonary artery for rabbits fed
cholesterol for up to 16 days are consistent with
the earlier work. Surprisingly, arterial
cholesterol accumulation in rabbits fed
cholesterol for 17 weeks was not related to the
cholesterol exposure index. It is possible that development
of fibrous caps over atheromatous
lesions50 limited the delivery of cholesterol
to arterial cells by reducing arterial LDL
degradation,51 thus uncoupling the relationship between
hypercholesterolemia and atherosclerotic lesion
development.
Model for Atherogenesis in Pulmonary Artery and
Aorta
Our data and that of others4 5 are consistent
with the hypothesis that atherogenesis proceeds at different rates in
the pulmonary artery and aortic arch at different stages of
atherogenesis: initially, the rate of cholesterol
accumulation in the pulmonary artery exceeds that in the aortic
arch, but at some later stage of atherogenesis, this rate slows and
becomes lower than that for the aortic arch. In comparison, this and
other studies1 6 11 12 20 21 22 23 show that atherogenesis in
the aortic arch and descending thoracic aorta of rabbits occurs in
parallel but at an increased rate in the aortic arch compared with the
descending thoracic aorta.
The high correlation between data for pulmonary artery and
aortic arch for cholesterol accumulation during the first
16 days of cholesterol feeding but the lack of such a
correlation after 17 weeks of cholesterol feeding might
suggest the following: mechanism(s) contributing to atherogenesis in
the pulmonary artery and aorta early after the onset of
cholesterol feeding are similar, but at later stages, the
mechanism(s) contributing to atherogenesis in these regions differ. A
companion study27 shows that the delivery of
cholesterol to cells of the pulmonary artery and
aortic arch via the degradation of LDL was similar in normal rabbits.
There were subtle changes in the interaction of LDL with these
arterial regions in rabbits fed cholesterol for
8 days, which, if exaggerated after longer periods of
cholesterol feeding, could contribute to the reduced rate
of cholesterol accumulation in the pulmonary artery
compared with the aortic arch at later stages of
atherogenesis.27 Alternatively or additionally, it is
possible that cholesterol efflux from the pulmonary
artery becomes more efficient than that from the aortic arch at later
stages of atherogenesis. Such changes in the mechanism(s) contributing
to atherogenesis in pulmonary artery and aortic arch could
provide an explanation for the apparent change in rate of progression
of atherosclerosis in these arterial
regions.
In summary, we found atheromatous lesion development in rabbits after 17 weeks of cholesterol feeding to be similar for the pulmonary artery and aortic arch and to be increased in the aortic arch compared with the descending thoracic aorta. Results from the first 16 days of cholesterol feeding were in partial agreement with the longer study; more cholesterol accumulated in the pulmonary artery and aortic arch than in the descending thoracic aorta. However, during the first 16 days of cholesterol feeding, cholesterol accumulation in the pulmonary artery exceeded that in the aortic arch. The results of the present study suggest that the relative rates of cholesterol accumulation in the pulmonary artery and the aortic arch differ at different stages of atheromatous lesion development. Such differences may indicate that the balance of processes delivering cholesterol to, and removing cholesterol from, arterial regions shifts in different ways in the pulmonary artery and the aortic regions during the development of atherosclerosis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-45027. Dr Schwenke is an Established Investigator of the American Heart Association. The author gratefully acknowledges the skillful technical assistance of Christina Tulbert, Elizabeth Ann Jordan, Deanna Warren, and John Mason.
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Footnotes |
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Reprint requests to Dawn C. Schwenke, PhD, Department of Pathology, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1072.
Received February 14, 1997; accepted June 6, 1997.
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