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Biomedical Engineering Department, Northwestern University, Evanston, Illinois 60208-3107; and Institute for Biomedical Engineering, University of California, San Diego, La Jolla, California 92093-0412
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Liu, S. Q. Regression of hypoxic hypertension-induced
changes in the elastic laminae of rat pulmonary arteries.
J. Appl. Physiol. 82(5):
1677-1684, 1997.
The elastic laminae of the pulmonary arteries
(PAs) undergo a progressive structural change in hypoxic hypertension.
This study focused on the reversibility of altered PA elastic laminae
of the rat due to hypoxic hypertension. The structure and
cross-sectional area of the PA medial elastic laminae were examined by
using electron-microscopic and image-analytic approaches during
recovery from 12 h and 10 days of hypoxic hypertension. At 12 h of
hypoxic hypertension, the elastic laminae, which appeared homogeneous
in normal control animals, were reorganized into structures composed of
randomly oriented filaments, with an increase in the cross-sectional
area of 70%. At 10 days of hypoxic hypertension, the elastic laminae
appeared homogeneous in structure and normal in cross-sectional area
despite continuous exposure to hypoxia. During recovery from 12 h of
hypoxic hypertension, the medial elastic laminae regained their
homogeneous structure and normal cross-sectional area after
day 2. During recovery from 10 days of
hypoxic hypertension, the medial elastic laminae changed from homogeneous to filamentous structures, with a progressively altered cross-sectional area that increased by 89% from recovery
day 0 to day
10 and returned to the normal level on
day 30. These changes were associated
with alterations in the PA wall tensile stress. These results indicated
that structural changes in the PA elastic laminae were reversible and
that the regression process depended on the duration of exposure to
hypoxia, the state of the elastic laminae, and possibly the tensile
stress level in the PA wall.
mechanical stress; vascular remodeling; electron
microscopy
INTRODUCTION HYPOXIC PULMONARY HYPERTENSION has been shown to induce
changes in the structure and function of the pulmonary arteries (PAs). At the molecular level, hypoxic hypertension modulates the regulation processes of growth-related genes, including the endothelin-1 and
endothelin receptor (2, 4, 9, 19), transforming growth factor- The reversibility of altered structure and function of the PAs due to
hypoxic hypertension has long been considered an important physiological and clinical issue. Previous studies showed that pathological changes in the structure of the endothelial and smooth muscle cells (14, 15, 28) as well as the contents of collagen and
elastin (15, 18) of the PAs can be completely or partially reversed
within a limited time of recovery. However, it is not clear whether
alterations in the structure of the PA elastic laminae are reversible.
The present study was designed to fill this gap and focused on the
regression process of hypoxic hypertension-induced alterations in the
PA elastic laminae.
On the basis of the fact that the PA elastic laminae experienced a
dynamic, stress-related change during the development of hypoxic
hypertension (10), it was hypothesized that the regression process of
this change might depend on the duration of exposure to hypoxia and the
state of the elastic laminae, as well as on the tensile stress level in
the PA wall. Thus, in this study, the regression process was initiated
at different times of hypoxic hypertension, when typical changes were
found in the elastic laminae, and was examined at selected times during
recovery.
METHODS Experimental procedures. Two series of
experiments were conducted with male 3-mo-old Sprague-Dawley rats.
First, the rats were exposed to hypoxia for 12 h followed by recovery
for 2 and 6 h and 1, 2, 6, and 10 days. Second, the rats were exposed
to hypoxia for 10 days followed by recovery for 4, 10, 20, and 30 days.
Data from 0 to 12 h and from 0 to 10 days of hypoxic hypertension were
cited from Ref. 10. The times 12 h and 10 days of hypoxia were defined
as recovery time 0 for the two series,
respectively. Five groups of normal rats were used as control animals
at 0, 2, 10, 20, and 40 days. Four rats were used at each time point. The number of rats in each group was estimated by using a
power-and-sample size testing method for the analysis of variance (27).
For the creation of hypoxic pulmonary hypertension, the rats were
placed in a hypoxic chamber with 10%
O2-90%
N2 at atmospheric pressure,
temperature 20°C, and 50% humidity (5, 10). The hypoxic
chamber was opened at a scheduled time daily for ~10 min for water
and food replenishment and bedding change. At the end of the
hypoxia-exposure periods, i.e., 12 h and 10 days, the animals were
transferred to room air for recovery. Normal control rats were housed
in the same room. Water and food were accessible at all times for the
hypoxic and normal rats.
At a scheduled time, each rat was anesthetized by an intraperitoneal
injection of pentobarbital sodium (50 mg/kg body weight). A
curve-tipped catheter was inserted into the PA trunk through the
jugular vein, right atrium, and right ventricle with a method described
by Stinger et al. (25) and Liu (10). The location of the catheter tip
was identified by monitoring the magnitude and pattern of the blood
pressure waves. Blood pressure at the PA trunk was recorded with a
Validyne pressure transducer. For the two groups of rats at 12 h and 10 days of hypoxic hypertension, blood pressure was measured inside the
hypoxic chamber with a technique described previously (10).
After the blood pressure measurement was made, each rat was heavily
anesthetized by an intraperitoneal injection of overdose pentobarbital
sodium after blood heparinization (200 U/kg body weight iv). The rat's
chest was opened, the PA trunk and trachea were cannulated, and the
lungs were inflated to an airway pressure of 10 cmH2O. The pulmonary blood vessels
were fixed by perfusion of 2.5% glutaraldehyde-0.1 M phosphate buffer
into the pulmonary vasculature with an inlet pressure equivalent to the
measured in vivo blood pressure at the PA trunk and a draining pressure of 3 mmHg at the pulmonary veins. After 1 h of fixation, two specimens were collected from the hilar pulmonary arteries of each rat for histological and electron-microscopic studies. These specimens were
placed in 2.5% glutaraldehyde-0.1 M phosphate buffer for 2 h, washed
with 0.1 M phosphate buffer, postfixed in 1% osmium tetroxide for 1 h
at 20°C, washed with distilled water, and dehydrated with graded
acetone (10, 30, 50, 70, 90, and 95% for 5 min each and 100% three
times for 10 min each) under rotation. The dehydrated specimens were
further treated with a mixture of 50% acetone and 50% Araldite resin
until sedimentation, embedded in pure Araldite resin, and cured for 12 h at 45°C, followed by another 12 h at 60°C. Six arterial
specimens were used to test the influence of specimen preparation on
the vessel dimensions. After fixation, dehydration, embedding, and
curing as described above, the arterial axial length was reduced by
11.7 ± 1.9% and the external diameter was reduced by 4.9 ± 1.6% compared with the dimensions of the fresh specimens.
For optical examination, transverse sections 1 µm thick were cut from
Araldite-embedded samples and stained with toluidine blue-O. The PA
medial, wall, and luminal areas were measured with the aid of an
Optimas image-processing system (BioScan, Edmond, WA), and the arterial
wall thickness and luminal diameter were calculated on the basis of
these measured areas (11). To evaluate the uniformity of the PA wall
thickness around the circumference, 20 PA transverse sections were
randomly selected, the PA wall thickness was measured at eight points
for each section around the circumference ~45° apart, and the
mean ± SD was calculated for the eight measurements of each
section. Results showed that the SD was ~3% of the mean for the
specimens with the most uniform wall thickness, whereas the SD was
~8% of the mean for the specimens with the least uniform wall
thickness (mean ± SD for this percentage was 5 ± 1.6%).
The average tensile stress in the arterial wall was calculated with the
equation For electron-microscopic examination, thin sections perpendicular to
the arterial longitudinal axis were cut with a diamond knife from the
same specimen block used for optical examination, stained with uranyl
acetate and lead citrate, and examined with a Philips 300 electron
microscope. Electron micrographs were collected from each specimen at
four points around the circumference of the arterial wall 90°
apart. Each micrograph (×2,000), containing a segment of the PA
media from the endothelium to the last layer of smooth muscle cells,
was further magnified to approximately ×14,000 with the Optimas
image-processing system. The area of each medial elastic lamina in an
electron micrograph was measured by hand tracing the laminal border
with the aid of the image-processing system, the areas of individual
elastic laminae were summed, and an area percentage of the elastic
laminae with respect to the total area of the media in this electron
micrograph was calculated (10, 13). The area percentages derived from
all electron micrographs of each specimen were averaged. The total area
of the elastic laminae in the entire transverse medial section of an
artery was calculated based on the calculated average area percentage
from the electron micrographs and the measured total transverse medial area from the optical histological sections as described above (10).
Electron micrographs of higher magnification (×6,000) were also
produced for the observation of the microstructure of the PA elastic
laminae.
Statistics. Means, SDs, and SEs were
calculated for all measured parameters. A statistical method, the
one-way analysis of variance, which is used for comparisons among
multiple groups (group number > 2), was employed to determine the
significance of difference among data collected at selected times
during recovery from hypoxic hypertension (27). The results of this
analysis, i.e., the F-ratios and
associated probability values, indicate the significance level of a
change during the entire course of observation. A change was considered
statistically significant at P < 0.05 (27).
RESULTS Changes in PA blood pressure. Figure
1 shows the changes in mean PA blood
pressure during recovery from 12 h and 10 days of hypoxic hypertension.
The PA blood pressure of the normal control rats did not change
significantly during the observation period (P > 0.05). In contrast, the PA
blood pressure increased from 13.7 ± 1.2 mmHg in normal
rats to 20 ± 0.5 mmHg at 12 h of hypoxic hypertension and to 22.4 ± 1.7 mmHg at 10 days of hypoxic hypertension. After the cessation
of hypoxia at 12 h and 10 days, the PA blood pressure in all hypoxic
rats decreased toward the normal level. These changes were
statistically significant (P < 0.0001). However, the rate of change in the PA blood pressure differed
considerably between these two series of recovery processes. The PA
blood pressure returned to the control level after 2 days of recovery
when the recovery process was initiated after 12 h of hypoxic
hypertension, whereas the PA blood pressure did not completely return
to the control level at 30 days of recovery when the recovery process was initiated at 10 days of hypoxic hypertension.
Changes in PA luminal radius and wall
thickness. Figure 2 shows
the changes in the PA luminal radius during recovery from 12 h as well
as 10 days of hypoxic hypertension. The luminal radius did not change
significantly during recovery from either 12 h (P > 0.05) or 10 days of hypoxic
hypertension (P > 0.05). The control
luminal radius did not change during the observation period (P > 0.05).
Figure 3 shows the changes in the PA wall
thickness during recovery from 12 h as well as 10 days of hypoxic
hypertension. For normal control rats, the wall thickness did not
change significantly during the observation period
(P > 0.05). At 12 h of hypoxic
hypertension, the PA wall thickness was not significantly different
from that of the normal control animals. During recovery from 12 h of
hypoxic hypertension, the PA wall thickness increased by ~9% within
the first several hours and decreased by ~21% on
day 10 compared with the peak
thickness (P < 0.05). On
day 10 of hypoxic hypertension, the PA
wall thickness increased significantly compared with the normal control
value. During recovery from 10 days of hypoxic hypertension, the PA
wall thickness decreased continuously and reached about the normal
level on day 30, with a total
reduction of ~33% of the peak thickness
(P < 0.0001).
Changes in PA wall tensile stress.
Figure 4 shows the changes in average
tensile stress of the PA wall during recovery from 12 h as well as 10 days of hypoxic hypertension. The average tensile stress of the normal
control PA walls did not change significantly during the observation
period (P > 0.05). After 12 h of
hypoxic hypertension, due to increased PA blood pressure, the wall
tensile stress increased significantly compared with the normal control values. During recovery from 12 h of hypoxic hypertension, the wall
tensile stress reduced rapidly and returned to the normal level within
2 days (P < 0.0001). At 10 days of
hypoxic hypertension, despite the existence of persistent PA
hypertension, the wall tensile stress returned to the normal level due
to wall thickening. During recovery from 10 days of hypoxic
hypertension, the wall tensile stress reduced below the normal level,
reached a limit after 10 days, and returned to the normal level after
30 days (P < 0.05).
Changes in the structure and cross-sectional area of
the PA elastic laminae. Figure
5 shows several electron micrographs of the
PA medial elastic laminae during recovery from 12 h of hypoxic hypertension. Normal elastic laminae appeared homogeneous under an
electron microscope. At 12 h of hypoxic hypertension, the PA elastic
laminae lost their homogeneous appearance and changed into structures
composed of randomly oriented filaments. This change was associated
with a significant increase in the thickness of the elastic laminae.
During recovery from 12 h of hypoxic hypertension, the filamentous
structure in the elastic laminae disappeared gradually, and the elastic
laminae regained their homogeneous appearance and normal thickness
after 2 days of recovery.
Figure 6 shows several electron micrographs
of the PA medial elastic laminae during recovery from 10 days of
hypoxic hypertension. At 10 days of hypoxic hypertension, the structure
of the elastic laminae appeared homogeneous and was similar to that of
the control elastic laminae. During initial recovery, the elastic
laminae were reorganized into structures composed of randomly oriented filaments with an increased thickness. After 10 days of recovery, the
thickness of the elastic laminae decreased gradually and returned to
the normal level on day 30, although
some filamentous structure remained.
Figure 7 shows the changes in total
cross-sectional area and percentage (with respect to the total medial
area) of the PA medial elastic laminae during recovery from 12 h as
well as 10 days of hypoxic hypertension. The cross-sectional area of
the elastic laminae in normal control arteries did not change
significantly from day 0 to
day 40 (P > 0.05). In contrast, this area
increased significantly at 12 h of hypoxic hypertension, decreased
rapidly during early recovery, and returned to the normal level after 2 days of recovery (P < 0.0001). At 10 days of hypoxic hypertension, the cross-sectional area
of the PA medial elastic laminae was not significantly altered compared
with the normal control value. During recovery from 10 days of hypoxic
hypertension, the area increased initially, reached a peak on
day 10, and returned to the control
level on day 30 (P < 0.0001). Similar changes were found in the area percentage of the PA elastic laminae during recovery
from 12 h (P < 0.05) as well as 10 days of hypoxic hypertension (P < 0.0001).
DISCUSSION Hypoxic pulmonary hypertension induces remodeling of the cells,
including the endothelial and smooth muscle cells and fibroblasts (1,
7, 14, 22) as well as the extracellular matrices, including collagen
and elastin, of the PAs (5, 15, 24). A recent study (10) showed that
hypoxic hypertension was associated with a dynamic change in the
ultrastructure of the PA elastic laminae. These laminae, which appeared
homogeneous under an electron microscope in normal controls, changed
into structures composed of randomly oriented filaments with an
increased volume from 2 h to 2 days of hypoxic hypertension and
regained their homogeneous structure and normal volume after 4 days
despite continuous exposure to hypoxia. A mechanical analysis showed
that the tensile stress in the pulmonary arterial wall increased
rapidly during early hypoxia due to elevated blood pressure, reached a
peak at 12 h, decreased after 48 h due to arterial wall thickening, and
returned to the control level after 4 days. This change coincided in
time course and correlated in magnitude with changes in the structure and volume of the PA elastic laminae. A further study demonstrated that
when nifedipine, a calcium-channel blocker, was administrated to the
hypoxic rats, no change was found in the blood pressure and tensile
stress, as well as in the structure and volume of the elastic laminae
of the PAs despite a continuous exposure to hypoxia (10). In another
study (unpublished data), a similar change was also found
in the elastic fibers of a rat vein graft, which experienced a step
increase in the tensile stress in the vessel wall due to exposure to
arterial blood pressure. These data suggested that altered tensile
stress played a role in the regulation of the remodeling process of the
PA elastic laminae in hypoxic hypertension.
The present study focused on the regression process of altered PA
medial elastic laminae during recovery from hypoxic hypertension. On
the basis of the mechanisms and dynamic features of the remodeling of
the PA elastic laminae during development of hypoxic hypertension, as
described in a previous study (10), it was expected that the regression
process might depend on several factors such as the duration of
exposure to hypoxia and the state of the elastic laminae as well as on
the tensile stress in the vessel wall. Thus two series of recovery
processes were initiated after 12 h and 10 days of hypoxic hypertension
because typical changes in the structure of the elastic laminae as well
as in the tensile stress level were found at these times (10).
As shown in the present results, different remodeling features were
found in the two series of regression processes. For the regression
process initiated at 12 h of hypoxic hypertension, the
elastic laminae, which expressed a filamentous appearance with an
increased volume at the beginning of the regression process, regained
their homogeneous structure and normal volume within 2 days of
recovery. For the regression process initiated at 10 days of hypoxia,
the elastic laminae, which appeared normal in structure and volume at
the beginning of the regression process, were reorganized into
filamentous structures with an increased volume at 10 days of recovery
and regained normal volume at 30 days, although random filaments still
existed. These results indicated that alterations in the structure of
the PA elastic laminae were reversible and that the regression process
depended on the duration of exposure to hypoxia and the state of the
elastic laminae.
Meyrick and Reid (15) studied the recovery process of the PA cells and
extracellular matrices after 10 days of exposure to hypoxia. By using
an electron-microscopic approach, they noticed a "fragmentation"
change in the PA medial elastic laminae at 3 days of recovery. This
fragmentation change was likely related to the filamentous
change in the PA elastic laminae as described in this study. However,
there was no detailed description of the structure of the fragmented
elastic laminae and the time course of this change in their study.
As shown previously (10), altered average tensile stress in the PA wall
was associated with remodeling of the elastic laminae during the
development of hypoxic hypertension. This stress is dependent on three
factors: blood pressure, luminal radius, and wall thickness of the
artery; i.e., stress = (pressure × radius)/thickness. During
recovery from hypoxic hypertension, the blood pressure as well as the
wall thickness decreased progressively, whereas the luminal radius of
the PAs did not change significantly. Thus a change in the average
tensile stress during recovery from hypoxic hypertension was mainly
related to the ratio of blood pressure to wall thickness.
At 12 h of hypoxic hypertension, the tensile stress increased to a peak
level due to a rapid increase in the PA blood pressure, without an
apparent change in the wall thickness. When a recovery process was
initiated at this time, the tensile stress decreased rapidly from the
peak to the control level, mainly due to a decrease in the PA blood
pressure. This change was associated with a rapid regression process of
altered elastic laminae. In consideration of previous findings that
increased tensile stress was related to the changes in the elastic
laminae (10), this result indicated that a reverse of the tensile
stress during early hypoxic hypertension (<12 h) contributed to the
regression of these laminae.
At 10 days of hypoxic hypertension, despite the existence of persistent
pulmonary hypertension, the tensile stress returned to the control
level due to increased PA wall thickness. When a recovery process was
initiated at this time, the tensile stress in the PA wall decreased to
a level below the control level during the initial 10 days of recovery
and returned to the control level at 30 days. The initial decrease in
the tensile stress was due to a more rapid decrease in blood pressure
than in wall thickness, whereas the following return was due to a
relatively more rapid decrease in wall thickness than in blood pressure
after 10 days of recovery. This downward biphasic change in tensile
stress was associated with a transient filamentous and volumetric
change in the elastic laminae during recovery. Although it was not
clear whether and how a lowered tensile stress influenced the structure of the elastic laminae, the present results suggested the possibility that a decrease in tensile stress from a control level, to which the
arteries adapted, might influence the conformation of the elastic
laminae and trigger a remodeling process. This implies that a
physiological tensile stress is necessary to maintain the stability of
the vascular elastic laminae, and any deviations, either an increase or
a decrease, may influence the structure of these laminae.
It should be pointed out that structural changes in the elastic laminae
during recovery from 10 days of hypoxic hypertension were similar to
those found during early hypoxic hypertension (10). Common changes
included filamentous appearance and increased volume. However, changes
during recovery lasted longer (from 4 to 30 days) than those found
during early hypoxic hypertension (from 2 h to 4 days). Whether these
similarities indicate an identical remodeling mechanism of the elastic
laminae during the development of and recovery from hypoxic
hypertension remains to be determined.
It is known that elastic laminae are composed of amorphous elastin and
elastin-associated microfibrils (6, 20, 21). In a physiological state,
the elastic laminae of the PAs appear amorphous under an electron
microscope (10, 20, 21). The filamentous structures that appeared in
the PA medial elastic laminae, as shown in the present study, indicated
that the microfibrils and elastin molecules in the elastic laminae
underwent a reorganization process during recovery from hypoxic
hypertension. This reorganization process might be associated with
fluid transport across the surface of these laminae, which was
indicated by a transient increase in the volume of the elastic laminae
during recovery from 10 days of hypoxic hypertension. The physiological
significance of these changes remains to be investigated.
(17),
platelet-derived growth factor (8), and angiotensin-converting enzyme
genes (16), and of several extracellular matrix genes, including the
fibronectin, type I procollagen, and tropoelastin genes (3, 23). At the
cellular and organ levels, hypoxic hypertension induces smooth muscle
cell proliferation (1, 7, 14, 22, 26), excessive collagen production, and wall thickening of the PAs (5, 15, 24). Recently, Liu
(10) demonstrated that an increase in the PA blood pressure due to exposure to hypoxia was associated with a rapid biphasic change in the structure of the PA elastic laminae. These laminae, which appeared homogeneous under an electron microscope in
normal control animals, changed into structures composed of randomly oriented filaments with an increased volume from 2 h to 2 days
and regained their homogeneous appearance and normal volume after 4 days of hypoxic hypertension. A mechanical analysis showed that changes
in the tensile stress in the PA wall due to hypertension coincided with
the time course and correlated in magnitude with the change in the
elastic laminae, indicating a role for tensile stress in the initiation
and regulation of the remodeling process. A further study demonstrated
that these changes influenced the mechanical function of the PAs during
early hypoxic hypertension (10).
= PR/H
(12), where is the average wall stress, P is measured blood
pressure in vivo, and R and
H are the radius and wall thickness,
respectively, of the PA.
Fig. 1.
Changes in pulmonary arterial (PA) blood pressure during recovery from
12 h (
) and 10 days (
) of hypoxic hypertension. 
, Normal
control blood pressure. Dotted line, hypoxia. Values are means ± SE.
[View Larger Version of this Image (13K GIF file)]
Fig. 2.
Changes in PA luminal radius during recovery from 12 h () and 10 days () of hypoxic hypertension. , Normal control radius. Dotted
line, hypoxia. Values are means ± SE.
[View Larger Version of this Image (11K GIF file)]
Fig. 3.
Changes in PA wall thickness during recovery from 12 h () and 10 days of hypoxic hypertension (). , Normal control wall thickness.
Dotted line, hypoxia. Values are means ± SE.
[View Larger Version of this Image (12K GIF file)]
Fig. 4.
Changes in average tensile stress in PA wall during recovery from 12 h
() and 10 days () of hypoxic hypertension. , Normal control
wall stress. Values are means ± SE.
[View Larger Version of this Image (12K GIF file)]
Fig. 5.
Electron micrographs showing normal medial elastic laminae (E) and
changes in structure of medial elastic laminae of PAs after 12 h of
hypoxia and during 0-6 h and 1-10 days of recovery (rec.) from 12 h of hypoxic hypertension. C, collagen fibers; S, smooth muscle
cell.
[View Larger Version of this Image (199K GIF file)]
Fig. 6.
Electron micrographs showing changes in structure of medial elastic
laminae of PAs during recovery from 10 days of hypoxic hypertension.
[View Larger Version of this Image (149K GIF file)]
Fig. 7.
Changes in total cross-sectional area of medial elastic laminae
(A) and percentage of medial elastic
laminae with reference to total medial area
(B) of PAs during recovery from 12 h
() and 10 days () of hypoxic hypertension. , Normal control
values. Values are means ± SE.
[View Larger Versions of these Images (12 + 12K GIF file)]
ACKNOWLEDGEMENTS
This research was supported by a grant from the Whitaker Foundation. Part of the work was done at the University of California, San Diego (La Jolla).
FOOTNOTES
Address for reprint requests: S. Q. Liu, Biomedical Engineering Dept., Northwestern Univ., 2145 Sheridan Rd,, Evanston, IL 60208-3107.
Received 19 August 1996; accepted in final form 14 January 1997.
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