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Biomedical Engineering Department, Northwestern University, Evanston, Illinois 60208-3107
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Liu, S. Q. Alterations in structure of elastic laminae
of rat pulmonary arteries in hypoxic hypertension. J. Appl. Physiol. 81(5): 2147-2155, 1996.
The effect
of hypoxic hypertension on the remodeling process of the elastic
laminae of the rat hilar pulmonary arteries (PAs) was studied by
electron microscopy. Rats were exposed to hypoxia (10%
O2) for periods of 0.5, 2, 6, 12, 48, 96, 144, and 240 h. Changes in the structure of the PA elastic laminae were examined and analyzed with respect to changes in the PA
wall tensile stress. The PA blood pressure increased rapidly within the
first several hours of hypoxia and reached a stable level within 2 days, whereas the PA wall tensile stress increased initially due to
elevated blood pressure and then decreased after 48 h due to vessel
wall thickening and returned to the control level after 4 days. In
association with these changes, the elastic laminae, which appeared
homogeneous in normal control rats, changed into structures composed of
randomly oriented filaments and edematous contents with an increase in
the volume during the early period of hypoxia and regained their
homogeneous appearance and normal volume after 4 days. The changes in
the elastic laminae were correlated with changes in the tensile stress.
These changes were associated with a transient decrease in the
stiffness of the PAs. In hypoxic rats given nifedipine, no change was
found in the blood pressure, the tensile stress, or the structure of
the elastic laminae of the PAs despite continuous exposure to hypoxia.
These results suggested that altered tensile stress in the PA wall
played a critical role in the initiation and regulation of structural
changes in the elastic laminae and that these changes might contribute to alterations in the mechanical properties of the PA in hypoxic hypertension.
elastic laminae; mechanical stress; hypoxic hypertension
INTRODUCTION IT HAS BEEN KNOWN for a long time that hypoxia induces
pulmonary hypertension, which is associated with changes in the
structure of the pulmonary arteries (PAs) at the molecular, cellular,
and organ levels. Recent studies have shown that hypoxic pulmonary hypertension can induce upregulation of several genes, including the
endothelin-1 and its receptor genes (15), the tropoelastin gene (34),
and the platelet-derived growth factor (PDGF)
A- and
B-chain genes (14) in the PAs and lung
tissues of several types of animals. As a result, cell hypertrophy and
hyperplasia (2, 6, 33), excessive collagen production (6, 26, 28), and
wall thickening of the PAs (6, 26) occur during the development of
hypoxic pulmonary hypertension. These studies have suggested that
altered mechanical stresses play a role in the initiation and
regulation of the remodeling process of the PAs in hypoxic
hypertension.
Supportive evidence for the role of the mechanical stress in the
regulation of vascular remodeling has been obtained with other types of
experimental models. For instance, a cyclic stretch in vitro can induce
upregulation of protooncogenes in cultured vascular smooth muscle cells
(SMCs) (23) and an increase in the synthetic rate of endothelial cell
cytoskeletal protein (37). A static stretch can promote DNA synthesis
of rat PAs in culture (39). Altered shear stress can modulate the
expression of several growth factor genes, including the basic
fibroblast growth factor and PDGF genes (24, 29) and the shape (21),
the orientation (27), and the cytoskeletal distribution (38) of
cultured endothelial cells. Shear stress also influences the rate of
proliferation and protein synthesis of arterial SMCs (35). In vivo
studies have shown that increased blood pressure in experimental
hypertension is associated with upregulation of growth promotor genes,
including the PDGF receptor (31),
TGF- Elastic laminae are the major elastic force-bearing constituents in
large blood vessels. On the induction of hypoxic pulmonary hypertension, the elastic laminae of large PAs are likely stretched and
deformed due to increased tensile stress. Thus it is reasonable to
hypothesize that increased tensile stress and strain in the PA wall may
induce a conformational change and initiate a remodeling process of the
elastic laminae. In the past, although extensive studies have been
carried out on the influence of altered mechanical stresses on the
remodeling process of the PAs, little attention has been given to the
elastic laminae, known as inert components in the vessel wall. The
present study was designed to verify the proposed hypothesis and
achieve the following goals: 1)
examine the remodeling process of the elastic laminae of the PAs under the influence of hypoxic hypertension,
2) evaluate the relationship between
the tensile stress in the PA wall and the degree of remodeling of the
elastic laminae, and 3) elucidate
the effect of altered elastic laminae on the mechanical properties of
the PAs.
METHODS Experimental procedures. Male 3-mo-old
Sprague-Dawley rats were used in the study. The rats were randomly
divided into 15 groups with 4 rats in each. Eight groups were exposed
to hypoxia (10% O2, 90%
N2, atmospheric pressure, 20°C
temperature, and 50% humidity) for periods of 0.5, 2, 6, 12, 48, 96, 144, and 240 h, respectively, by using a method described previously
(6). One group was used to monitor the initial effect of hypoxia on the PA blood pressure. Three groups were exposed to hypoxia of the same
condition as described above for periods of 2, 12, and 48 h and
simultaneously given nifedipine, a calcium-channel blocker and
hypertension suppressor. The remaining three groups were kept in room
air and used as controls at times of 0, 48, and 240 h.
For the study of the initial effect of hypoxia on the PA blood
pressure, each rat was anesthetized by an intraperitoneal injection of
pentobarbital sodium (50 mg/kg body wt). A catheter with a curved tip
was inserted into the PA trunk through the jugular vein, right atrium,
and right ventricle by using a method described by Stinger et al. (36).
The location of the catheter tip was identified by monitoring the
magnitude and pattern of the blood pressure trace. The blood pressure
at the PA trunk was recorded with a Validyne pressure transducer. The
rat was then placed into the hypoxic chamber, and the PA blood pressure
was continuously recorded. The pressure at 5 min of exposure to hypoxia
was considered the initial value of blood pressure.
For the study of the effect of hypoxic hypertension on the PAs, each
rat was anesthetized at a scheduled time and the PA blood pressure was
measured with the method described above. The right carotid artery was
isolated, and a micro-thermometer of diameter 0.5 mm (Cole-Parmer,
Niles, IL) was inserted through the carotid artery into the ascending
aorta for cardiac output measurements by using a thermodilution method
described previously (11). The PA catheter was retreated to the right
ventricle, 0.2-ml saline of 20°C was rapidly injected into the
right ventricle, the blood temperature at the ascending aorta was
continuously recorded with a Cole-Parmer temperature recorder, the
temperature curve was analyzed, and the cardiac output was calculated
with a method described previously (11). Cardiac index was calculated
as the ratio of the cardiac output to the animal body weight with a
unit of milliliters per kilogram per minute (12). All hemodynamic measurements for hypoxic rats were carried out inside the hypoxic chamber.
To distinguish the effect of altered tensile stress from other factors
such as lowered blood O2 tension,
nifedipine (Pfizer, Parsippany, NJ) was used to prevent pulmonary
hypertension when rats were continuously exposed to hypoxia (32).
Nifedipine was diluted in polyethylene glycol and administrated
intraperitoneally three times per day (total daily dosage of 15 mg/kg).
For each rat, the first administration was given 2 h before the rat was placed into the hypoxic chamber, followed by additional administrations every 8 h until the rat was killed for examination. The PA blood pressure and cardiac output were measured at scheduled times by using
methods described above.
After hemodynamic measurements, each rat was heavily anesthetized by an
intraperitoneal injection of an overdose of pentobarbital sodium after
blood heparinization. The rat chest was opened, the PA trunk and the
trachea were cannulated, and the lungs were partially inflated,
excised, and placed in a Krebs solution bath. The hilar arteries of the
right lung were used for electron microscopic observations, and those
of the left lung were used for the evaluation of the mechanical
properties of the PAs.
Electron microscopy. For the
collection of the electron microscopic specimens, the
right lung was inflated to airway pressure of 10 cmH2O and the pulmonary blood
vessels were fixed by perfusion of 2.5% glutaraldehyde/0.1 M phosphate
buffer through the pulmonary vasculature for 1 h with perfusion
pressure identical to the in vivo measured blood pressure at the PAs
and draining pressure of 3 mmHg at the pulmonary veins. Specimens were
collected from the right hilar PAs of each rat, placed in 2.5%
glutaraldehyde/0.1 M phosphate buffer for another 2 h, washed with 0.1 M phosphate buffer, postfixed in 1% osmium tetroxide for 1 h at
20°C, washed with distilled water, dehydrated with graded acetone,
and embedded in Araldite for histological and electron microscopic
studies.
Thin sections perpendicular to the arterial longitudinal axis were cut
with a diamond knife, stained with uranyl acetate and lead citrate, and
examined with a Philips 300 electron microscope. Electron micrographs
were collected from each specimen at four regions of the arterial wall
90° apart. Each micrograph (×2,000), containing the entire
arterial media, was further magnified to approximately ×14,000
through an image-processing system. The area of the medial elastic
laminae on each electron micrograph was measured with the aid of an
Optimas image-processing system (BioScan, Edmonds, WA), and
the total area of the medial elastic laminae in the entire cross
section of an artery was calculated based on the measured arterial wall
cross-sectional area (18). A percentage of the medial elastic laminae
was calculated with respect to the total medial area. Electron
micrographs of higher magnification (×6,000) were also produced
for the observation of the microstructure of the elastic laminae.
Mechanical analysis. For the
calculation of the average tensile stress in the PA wall, histological
sections of 1 µm in thickness were cut from Araldite-embedded samples
and stained with toluidine blue O. The arterial wall and lumen areas of
the PAs were measured with an Olympus microscope and an Optimas
image-processing system, and the arterial wall thickness and lumen
diameter were calculated on the basis of the measured areas. The
average tensile stress in the arterial wall was calculated with the
Laplace equation
1 (10), and insulin-like
growth factor genes (4); hyperplasia and hypertrophy of SMCs (1, 3);
excessive production of collagen; and wall thickening of systemic
arteries (1, 3, 5, 16). A recent study showed that the remodeling
process of the arterial cells and extracellular matrices was dependent
on local mechanical factors in animal hypertension (20). Thus
mechanical stresses have been increasingly considered as regulatory
factors for vascular growth and remodeling.
where
(1)
is tensile stress, P is measured blood pressure in vivo, and
R and
H are the radius and wall thickness of
the PAs, respectively.
For the determination of the stress-strain relationship, the main left PA tree was dissected for several generations and the side branches of the tree were ligated with fine sutures. The isolated arterial tree was placed in a Krebs solution bath aerated with a mixture of 95% O2-5% CO2 and cannulated with a polyethylene tubing. The vessel was inflated and deflated for several cycles from 0 to 30 mmHg by using 6% Dextran/Krebs solution and was then inflated continuously from 0 to 30 mmHg. Changes in the vessel diameter and length between two selected side branches and the inflation pressure were recorded with a video and physiological signal-recording system during the inflation process. The diameter and length of the PAs were measured at selected inflation pressures with the aid of an image-processing system.
After inflation tests, a segment was excised from the middle portion of the vessel, cut open longitudinally to release residual stresses (16, 17), and embedded in 15% gelatin/Krebs solution at 37°C. The gelatin-embedded specimen was placed in a refrigerator. On solidification of the gelatin solution, a cube-shaped gel, with the arterial specimen embedded inside, was trimmed, mounted to a cryo-microtome with the vessel cross section parallel to the knife edge, and cut into sections of 10-20 µm in thickness. The gelatin embedding technique was used to maintain the zero-stress configuration of the arterial specimens. The internal and external circumferential lengths of the section were measured by using an image-processing system. These lengths were used as the zero-stress references for strain calculation. The average circumferential strain at each inflation pressure was calculated with reference to the zero-stress state of the specimen by using a method described previously (7, 19), and the corresponding circumferential stress was calculated by using the Laplace equation for a cylindrical tube.
Statistics. Means and SD and SE values were calculated for measured parameters. A statistical method, one-way analysis of variance used for multiple comparisons (40), was employed to determine the significance of differences in each variable between data collected at different times. Differences were considered statistically significant at P < 0.05.
RESULTS
Blood pressure and cardiac index.
Figure 1 shows changes in the mean PA blood
pressure of hypoxic and control rats. The blood pressure of the control
rats did not change from 0 to 240 h (P > 0.05). In contrast, the blood pressure of the hypoxic rats
increased from the control value from 14 ± 1 to 18 ± 2 mmHg
within 5 min of exposure to hypoxia, continued to increase to 20 ± 2 mmHg at 48 h, and relatively stabilized afterward. The change in the
PA blood pressure was statistically significant during the development of hypoxia (P < 0.0001). When
nifedipine was administrated to the hypoxic rats from time 2 h to 48 h, the PA blood pressure did not change
significantly (P > 0.05).
Figure 2 shows changes in the cardiac index
of hypoxic and control rats. The cardiac indexes of the control and
hypoxic rats with and without nifedipine did not change significantly
from 0 to 240 h (P > 0.05 for all
groups).
Lumen radius and wall thickness. The
PA lumen radii of both hypoxic ad control rats did not change
significantly (P > 0.05 for both)
from 0 to 240 h of exposure to hypoxia (see Fig.
3). The PA wall thickness of the control
rats did not change, whereas that of the hypoxic rats increased
significantly after an initial period of 12 h
(P < 0.0001) and stabilized
relatively after 144 h of exposure to hypoxia (see Fig.
4). Figure 5
shows several electron micrographs of the PAs at selected times of
hypoxia. Cell hyperplasia, excessive collagen production, and wall
thickening are evident, especially from 96 to 240 h of hypoxia. In
hypoxic rats administrated with nifedipine, the lumen radius and wall thickness did not change significantly from 2 to 48 h
(P > 0.05 for both).
Average wall tensile stress. Figure
6 shows the average tensile stress in the
PA wall of hypoxic and control rats. The average stress of the control
rats did not change significantly from 0 to 240 h
(P > 0.05), whereas that of the
hypoxic rats increased rapidly during the initial 2 h of exposure to
hypoxia, reached a peak at 12 h, decreased afterward, and returned to
the control level at 144 h (P < 0.0001). In hypoxic rats administrated with nifedipine, the average
tensile stress did not change significantly from 2 to 48 h
(P > 0.05).
Remodeling of PA elastic laminae.
Figure 7 shows several electron micrographs
of the medial elastic laminae of the PAs in control and hypoxic rats at
different times. The thickness of the elastic laminae increased rapidly
from 30 min to 12 h of exposure to hypoxia and then gradually decreased
to about the control level at 144 h. From 30 min to 6 h, edematous
contents appeared in the elastic laminae in the electron micrograph. At
12 h, the elastic laminae, which appeared homogeneous in normal control
rats, changed into structures composed of randomly oriented short
filaments embedded in edematous contents. The density of the filaments
increased at 48 h in association with a gradual decrease in the wall
thickness. The filamentous structures disappeared at 96 h of exposure
to hypoxia before the thickness of the elastic laminae returned to the
control level. All elastic laminae across the PA media underwent this
type of change, although the internal elastic lamina experienced a
change of a larger degree than other laminae (see Fig. 5,
top center).
When nifedipine was administrated to hypoxic rats intraperitoneally for periods of 2, 12, and 48 h, the thickness and structure of the elastic laminae did not change compared with normal control rats (see Fig. 7J). In control rats administrated with nifedipine for 48 h, the structure of the elastic laminae did not change significantly.
Figure 8A shows changes in the cross-sectional area of the total medial elastic laminae of the PAs of control and hypoxic rats with and without administration of nifedipine. In the control rats, the area of the elastic laminae did not change significantly from 0 to 240 h (P > 0.05). In contrast, the area of the elastic laminae of the PAs in the hypoxic rats increased rapidly within 12 h of hypoxia, decreased afterward, and returned to the control level at 4 days. This change was statistically significant (P < 0.0001). In the hypoxic rats administrated with nifedipine for periods of 2, 12, and 48 h, no change was found in the areas of the elastic laminae (P > 0.05). Figure 8B shows changes in the percentage of the elastic laminae calculated with respect to the total medial area for the control and hypoxic rats with and without administration of nifedipine. The time course of the change for each group was similar to that of the area of the elastic laminae.
Figure 9 shows a correlation between the
average tensile stress and the total cross-sectional area of the PA
elastic laminae of hypoxic and control rats. It was found that the
magnitude of the change in the tensile stress was significantly
correlated with that of the cross-sectional area of the elastic laminae
during the development of hypoxia.
Remodeling of mechanical properties.
Figure 10 shows several circumferential
stress-strain curves of the PAs in hypoxic and control rats. The PA
stress-strain curve shifted up at 2 to 12 h in hypoxic compared with
control rats and shifted back toward the control level from 4 to 10 days. At a given stress value, the PAs at 2 and 12 h of
hypoxia experienced a larger deformation than the control arteries,
indicating a decrease in the stiffness of the vessel wall.
DISCUSSION
The present study focused on the effect of altered tensile stress on the structure of the PA elastic laminae in hypoxic hypertension. Our results showed that changes in the structure and volume of the elastic laminae were coincident in time course and correlated in magnitude with that in the average tensile stress in the PA wall. The structural change in the elastic laminae occurred only when the tensile stress in the PA wall exceeded the control level. In another study, Liu and Fung (unpublished observations) showed that a suddenly increased tensile stress in the vein graft wall due to exposure to arterial blood pressure induced a similar change in the elastic fibers of the grafts. These results suggested that tensile stress played a critical role in the initiation and regulation of the remodeling process of the vascular elastic laminae.
It should be addressed that endothelial edema and blebs were also found in the PAs within 12 h of hypoxia (6) in addition to changes in the elastic laminae. However, no apparent change was found in other components during the early period of hypoxia. Proliferation of SMCs and fibroblasts as well as excessive production of collagen fibers were found after 2 days of hypoxia. Unlike the elastic laminae, these relatively late changes existed through the observation period after 2 days. These changes contributed significantly to the late thickening process of the PA wall. It was possible that the early transient thickening process of the elastic laminae might serve to mitigate the suddenly increased PA wall tensile stress before the initiation of wall thickening due to cell proliferation and extracellular matrix production.
In hypoxia-induced hypertension, the mechanics of the PAs was characterized by a biphasic change in the vessel wall tensile stress. It is well known that the average tensile stress in an arterial wall is determined by the blood pressure, the lumen radius, and the wall thickness, i.e., stress = pressure × radius/thickness. Because in hypoxic hypertension the lumen radius did not change significantly (see Fig. 3), the biphasic time course of the tensile stress reflected a change in the ratio of the blood pressure to the wall thickness. The early increase in the tensile stress from 0 to 12 h was mainly due to a rapid elevation in the blood pressure without an apparent change in the wall thickness, whereas the late decrease from 12 to 144 h was mainly due to arterial wall thickening without further apparent elevation in the blood pressure (see Figs. 1, 4, and 6). The rate of PA wall thickening diminished gradually despite persistent hypertension when the tensile stress returned toward the control level. These results suggested that the tensile stress, not the blood pressure, might serve as a pivotal factor in the regulation of arterial thickening in response to hypertension.
Shear stress, another major mechanical factor, has been shown to modulate the remodeling process of a variety of cell types (21, 24, 27, 29, 35, 38) and vascular intima (8). Thus shear stress should be hypothetically considered a factor in the regulation of the remodeling of the elastic laminae. In the model of hypoxic pulmonary hypertension, a key question for the shear-related issues is whether the blood flow rate, which determines the shear stress on the endothelial cell surface, is affected by hypertension in the vessels of observation. Due to difficulties in direct flow measurements in the hilar PAs of a living animal, cardiac output was measured instead and used to indicate whether there existed a change in the blood flow rate. For the PA trunk, the cardiac output is exactly the blood flow rate in this vessel. For the hilar PAs, although the cardiac output does not represent the blood flow rate in each vessel, it can be used as an indicator of a flow change, provided that the flow distribution to different hilar arteries remains constant. In the present study, a systematic measurement showed that no apparent change was found in the cardiac output of the hypoxic rats, indicating that the blood flow rate, or the shear stress on the endothelial cell surface, of a large PA was not significantly influenced by hypoxic hypertension. This result was consistent with that from a previous study by Hassoun et al. (12). Thus the possibility of the shear effect on the remodeling process of the elastic laminae can be excluded in the model of hypoxic hypertension.
Hypoxia, without the involvement of hypertension, has been shown to induce upregulation of vascular endothelial growth factor, a potent mitogen, in several cell types (22). Thus there is a possibility that hypoxia per se may contribute to the remodeling process of the elastic laminae. To examine whether this was the case, nifedipine, a calcium channel blocker, was used to prevent hypertension in the hypoxic rats (32) so that the influence of lowered O2 tension could be evaluated. Because significant changes in the structure of the elastic laminae occurred during 2-48 h of exposure to hypoxia, nifedipine was only administrated during this period when the rat was continuously exposed to hypoxia. In such cases, neither the PA blood pressure nor the structure of the elastic laminae changed significantly, despite the existence of lowered blood O2 tension. Thus the effect of hypoxia per se on the elastic laminae was negligible.
The mechanical analysis in this study showed that the stiffness of the PAs decreased considerably during the early period of hypoxia, when changes in the structure of the elastic laminae occurred. Elastic laminae are known as elastic and force-bearing constituents of blood vessels. It was possible that structural changes in the elastic laminae contributed to the softening process of the PAs during early hypoxia. However, hypoxic hypertension also induced remodeling of cells and other types of extracellular matrices, such as formation of bleb and edema in the endothelial cell during early hypoxia (6) and hyperplasia of SMCs and fibroblasts and excessive production of collagen fibers during late hypoxia (Fig. 5; Refs. 2, 6, 26, 28, 33). These remodeling processes might also contribute to alterations in the mechanical properties of the PAs.
It is known that elastic laminae are composed of amorphous elastin and elastin-associated microfibrils (9, 30). In a physiological state, the elastic laminae of blood vessels appear amorphous under an electron microscope (30). In hypoxic hypertension, as shown in the present study, the elastic laminae appeared as structures composed of short randomly oriented filaments during the period from 12 to 48 h of exposure to hypoxia, when the arterial tensile stress exceeded the control level. This result suggested that the structure of the elastin and microfibrils was reorganized under the influence of altered tensile stress. The increased tensile stress might also trigger fluid transport across the elastic laminae. This was indicated by a transient change in the volume of the elastic laminae as shown in this study. In a previous study (6), it was found that the elastic laminae of the PAs were unable to be stained during the period from 0.5 to 48 h of exposure to hypoxia with a conventionally used staining agent toluidine blue O that stains the elastic laminae dark blue in normal blood vessels. Conformational alterations in the elastic laminae may be responsible for this histochemical change.
The remodeling process of the elastic laminae of the PAs may not only involve structural but also metabolic changes. In a previous study, Poiani et al. (28) showed a transient increase in the rate of elastin synthesis in the PAs in early hypoxic hypertension. Maruyama et al. (25) showed an increase in the elastolytic activity in the PAs during the early period (2 days) of hypoxic hypertension. These biochemical changes in the elastin may be related to the structural change in the elastic laminae under the influence of altered tensile stress, as observed in this study.
ACKNOWLEDGEMENTS
This research was supported by a grant from the Whitaker Foundation and an initiation grant from the Northwestern University. Part of the work was done at the University of California, San Diego.
FOOTNOTES
Address for reprint requests: S. Q. Liu, Biomedical Engineering Dept., Northwestern Univ., 2145 Sheridan Rd., Evanston, IL 60208-3107.
Received 15 December 1995; accepted in final form 10 July 1996.
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