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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Prostacyclin (PGI2) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI2 receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI2 and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.
Key Words: knockout mice; prostacyclin receptor; pulmonary hypertension; chronic hypoxia
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in most animal species (1), but the magnitude of pulmonary hypertension and the degree of vascular remodeling are species (1) and strain (8) dependent. The development of pulmonary hypertension and the muscularization of the precapillary pulmonary arteries can be inhibited by treatment of animals with a calcium entry blocker (9), by treatment with a platelet-activating factor (PAF) antagonist that does not affect hypoxic pulmonary vasoconstriction (10), or in transgenic mice that overexpress the prostacyclin (PGI2) synthase gene in a lung-specific manner (11). However, the molecular and cellular mechanisms of vascular remodeling in hypoxic pulmonary hypertension are poorly understood.
PGI2 is a potent pulmonary vasodilator and chronic intravenous infusion of PGI2 is being used successfully in the treatment of patients with severe pulmonary hypertension (12, 13). Chronic PGI2 treatment can reduce the pulmonary vascular resistance in patients with primary pulmonary hypertension (14) and PGI2 attenuates the proliferation of cultured vascular smooth muscle cells (15) through signal transduction following ligand binding to its receptor. We found that patients with severe pulmonary hypertension have reduced PGI2 receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle (16). The question of whether endogenously produced PGI2 modulates pulmonary vascular remodeling has been of interest for some time (17, 18) but could not be rigorously addressed because of the lack of specific PGI-R antagonists. Instead of applying pharmacological tools we employed the recently developed PGI-R knockout (KO) mouse model (19) to address the question of PGI-R-dependent lung vascular remodeling. Here we report on comparative studies with wild-type (WT) and PGI-R KO mice and show that after exposure of the animals to chronic hypobaric hypoxia, PGI-R KO mice develop a greater degree of pulmonary hypertension and pulmonary arterial media thickening than WT mice. Our data underscore the importance of PGI2 in the modulation of the pulmonary vascular response to chronic hypoxia.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Animals
Prostacyclin receptor (PGI-R) knockout (KO) mice (19) were first backbred into the C57BL/6 background for six generations in Kyoto, Japan. Upon arrival in Denver, the animals were back-crossed four more generations to maintain a congenic strain. For all experiments, homozygous null mice were used.
Hypobaric Hypoxic Exposure
For exposure to hypobaric hypoxia, 8-wk-old male PGI-R KO mice (19) (n = 10) and WT C57BL/6 (n = 18) mice were housed in a hypobaric chamber for 3 wk at a simulated altitude of 17,000 ft (Pb = 410 mm Hg; inspired PO2 = 76 mm Hg). Ten KO and 10 WT animals were kept at Denver altitude (5,280 ft; Pb = 630 mm Hg, inspired PO2 = 122 mm Hg) for more than 5 wk.
Acute Hypoxic Exposure
To compare the effect of acute hypoxia on right ventricular pressure of the KO mice (n = 8) with that of WT animals (n = 8), male mice 8 wk old were placed in an acrylic chamber (fraction of inspired oxygen [FIO2] = 0.1) at Denver altitude for 15 min (11). During pressure measurement, the animals were maintained in the hypoxic environment with flow-by oxygen at FIO2 = 0.1.
Measurement of Right Ventricular Pressure
Hemodynamic assessment was performed as previously described by direct measurement of right ventricular systolic pressure (RVSP) (11, 20). After RVSP measurement, lung tissue was inflated with low-melt agarose and fixed with 10% buffered formalin.
Hematocrit Analysis
Spun hematocrit was measured collecting 0.2 ml of blood by way of ventricular puncture.
Assessment of Right Ventricular Hypertrophy
The hearts were fixed with 10% buffered formaldehyde for 24 h. The right ventricular free wall (RV) and the left ventricle together with the septum (LV + S) were weighed separately, and RV/(LV + S) was calculated.
Histology and Morphometric Analysis
A representative hematoxylin and eosin-stained lung section through
the hilum was coded and blindly evaluated for remodeling of pulmonary arteries in the range of 30-50 µm as previously described (11). The
wall thickness of each artery was expressed as percentage of the vessel
diameter by the formula (Ed 
Id)/Ed (VWT) (Ed, external diameter;
Id, internal diameter; VWT, vessel wall thickness). For the conditions
of control (Denver altitude) and chronic hypoxia, each experimental
animal was examined (n = 10 for KO kept at Denver altitude; n = 10, WT at Denver altitude; n = 9, KO exposed to chronic hypobaric hypoxia; n = 13, WT, chronic hypobaric hypoxia). Between 10 and 20 measurements were made per animal and the average was calculated.
Immunohistochemistry
Histological sections were heated in 1× citrate buffer for 15 min, followed by H2O2 block of endogenous peroxidase for 15 min. The sections were then incubated with anti-smooth muscle 
-actin antibody
at 37° C for 30 min, followed by Quickkit (Vector, Burlingame, CA)
for 10 min at room temperature.
Statistical Analysis
All values were expressed as means ± SEM. Means of several groups were compared by unpaired t tests using Microsoft Excel 2000. For correlation data, a Pearson r correlation coefficient was calculated using GraphPad Prism 3.01 for Windows 2000 (GraphPad Software Inc., San Diego, CA). Two-tailed parametric analysis was considered significant when p < 0.05.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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PGI-R Knockout Does Not Cause Pulmonary Hypertension at Denver Altitude
At baseline (Denver altitude; Pb = 630 mm Hg, inspired PO2 = 122 mm Hg) PGI-R KO (n = 10) and WT (n = 10) mice displayed no difference in RVSP (31.6 ± 1.3 mm Hg versus 28.0 ± 1.0 mm Hg; not significance [ns]) (Figure 1).
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PGI-R Knockout and WT Mice Exhibit a Similar Hypertensive Response to Acute Hypoxia
During acute hypoxia, KO (n = 8) and WT (n = 8) mice show a comparable RVSP (32.7 ± 0.9 mm Hg versus 29.8 ± 1.0 mm Hg; ns) (Figure 1).
PGI-R KO Mice Develop More Severe Pulmonary Hypertension after Chronic Hypobaric Hypoxia Than WT Animals
After 3 wk of exposure to hypobaric hypoxia, KO animals (n = 9) developed significantly more severe pulmonary hypertension, with the RVSP averaging 44.9 ± 2.4 mm Hg when compared with the WT animals (n = 13), which had an average RVSP of 35.6 ± 1.5 mm Hg (Figure 1).
Both PGI-R KO and WT Animals Demonstrate a Comparable Polycythemic Response with Exposure to Chronic Hypobaric Hypoxia
At Denver altitude, the PGI-R KO animals (n = 10) had a slightly lower hematocrit than did WT animals (n = 10) (48.8 ± 0.4% versus 51.5 ± 1.1%; p = 0.02). In response to chronic hypobaric hypoxia, both PGI-R KO (n = 9) and WT animals (n = 13) developed polycythemia when compared with Denver altitude control animals (57.7 ± 1.4% versus 48.8 ± 0.4% for PGI-R KO, p = 0.0001, and 55.0 ± 1.0% versus 51.5 ± 1.1% for WT, p = 0.02). The extent of polycythemia was the same for KO and WT animals after chronically hypobaric hypoxic exposure (57.7 ± 1.4% versus 55.0 ± 1.0%, ns).
PGI-R KO Mice Have More Severe Right Ventricular Hypertrophy after Chronic Hypobaric Hypoxia Than Do WT Animals
At Denver altitude, KO (n = 10) and WT (n = 10) mice had similar RV/(LV + S) values (0.26 ± 0.01 versus 0.26 ± 0.003; ns). After 3 wk of hypobaric hypoxic exposure, KO animals (n = 9) had significantly higher RV/(LV + S) than did WT animals (n = 13) (0.40 ± 0.01 versus 0.31 ± 0.01; p = 0.0001) (Figure 2).
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PGI-R KO Mice Have Pulmonary Vascular Remodeling after Hypobaric Hypoxia
At Denver altitude, KO and WT animals showed no morphological differences in pulmonary artery medial wall thickness
in the vessels that expressed smooth muscle cell -actin (Figure
3A, WT at Denver altitude; B, KO at Denver altitude). After
chronic exposure to hypobaric hypoxia, WT animals developed no medial wall hypertrophy (Figure 3C; WT, hypoxia),
whereas KO animals had significant medial wall thickening
(Figure 3D; KO, hypoxia). The statistical analysis of the lung
vascular morphometry also revealed that at baseline in Denver, KO (n = 10) and WT (n = 10) animals did not differ in
vessel wall thickness of the pulmonary arteries in the size range
of 30-50 µm in external diameter (0.172 ± 0.010 versus 0.164 ± 0.004; ns), and that chronic hypobaric hypoxia caused no vessel wall hypertrophy in WT animals (n = 13, 0.165 ± 0.005)
whereas significant vessel wall thickening occurred in KO animals (n = 9, 0.228 ± 0.010; p = 0.0002) (Figure 4).
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RVSP and RV/(LV + S) of All Animals Demonstrate a Significant Correlation
Plotting RV/(LV + S) against RVSP demonstrates the correlation of right ventricular hypertrophy to elevated RVSP. Both types of animals (WT and KO) have a significant correlation between RVSP and RV/(LV + S) (data not shown). When plotted as a group, Pearson r and two-tailed p value of the correlation were 0.75 and less than 0.0001 (Figure 5).
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Vessel Wall Thickening Correlates with RVSP Only in the PGI-R KO Mice, But Not in the WT Mice
When RVSP was plotted against VWT, there was a significant correlation only in the PGI-R KO mice (Pearson r, 0.60; two-tailed p value, 0.0067; Figure 6b). There was no significant correlation between vessel wall thickening and RVSP in the WT animals (Pearson r, 0.03; two-tailed p value, 0.90, ns; Figure 6a). The statistical analysis also revealed that the correlation coefficient of the KO mice between vessel wall thickening and RVSP was significantly different from that of the WT mice (p < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The principal findings of this study are that PGI-R KO mice developed a greater degree of pulmonary hypertension, more right ventricular hypertrophy, and pulmonary vascular remodeling after chronic exposure to hypobaric hypoxia than WT mice. Our data indicate that PGI2 and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling and that the absence of a functional PGI2 receptor worsens hypoxic pulmonary hypertension.
PGI2 reduces pulmonary vascular resistance (14) and attenuates proliferation of cultured vascular smooth muscle cells (15) through signal transduction following ligand binding to its receptor. We previously found that patients with severe pulmonary hypertension had a reduced PGI-R expression in the remodeled pulmonary arterial smooth muscle (16), and we hypothesized that PGI-R KO animals would have a greater degree of pulmonary hypertension and more pronounced lung vascular remodeling when compared with WT animals. The results of this study are consistent with this hypothesis. At Denver altitude, the PGI-R KO did not develop pulmonary hypertension, right ventricular hypertrophy, or lung vascular wall thickening when compared with their WT counterparts. However, after 3 wk of hypobaric hypoxia, PGI-R KO mice developed more severe pulmonary hypertension and right ventricular hypertrophy when compared with the WT animals (Figures 1 and 2). Chronic hypobaric hypoxia caused pulmonary vascular remodeling in the PGI-R KO mice but not in the WT mice (Figures 3 and 4). The finding that the C57BL/6 WT strain that was used in this study does not show pronounced pulmonary vascular remodeling in response to chronic hypoxia (20) has been confirmed by our present study and thus the vascular remodeling triggered by chronic hypobaric hypoxia in the C57BL/6 PGI-R KO animals is remarkable. Wild-type C57BL/6 mice show no correlation between RVSP and vessel wall thickness (a measurement of remodeling), whereas PGI-R KO mice show a significant correlation between these two parameters (Figure 6a and 6b).
A generally accepted paradigm in rat models of hypoxic pulmonary hypertension is the correlation between mean pulmonary artery pressure (measured by catheterization) and right ventricular hypertrophy, as assessed by RV/(LV + S) (5). This has not, to our knowledge, been previously demonstrated in murine models. In the current work, we demonstrate that for both WT and PGIR-KO mice, a good correlation exists between RVSP (an indirect measure of pulmonary artery pressure) and the development of right ventricular hypertrophy (Figure 5).
Narumiya and associates have previously characterized the PGI-R KO mice and shown their increased susceptibility to thrombosis and reduced inflammatory and pain responses (19, 21). We now add new data to characterize this PGI-R KO phenotype further.
The lack of PGI-R signaling as demonstrated in these animals previously (19, 21) could augment chronic hypoxic vasoconstriction, impair mechanisms that protect against pulmonary vascular remodeling, or facilitate vascular cell growth.
The acute hypoxia-induced pulmonary presser response was
not enhanced in the PGI-R KO animals, and the hematocrit in
both the PGI-R and the WT animals did not differ following
exposure to hypobaric hypoxia. Therefore, a change in hypoxic vasoconstriction or a change in blood viscosity is unlikely
to account for the greater degree of pulmonary hypertension and vascular remodeling in the PGI-R KO mice. The work
presented here is important because it shows for the first time
that there is clearly a membrane prostacyclin receptor-dependent element to modulation of the lung vascular remodeling.
A rigorous assessment of the importance of PGI-R in modulating lung vascular structure has previously not been possible
due to the lack of a specific prostacyclin receptor antagonist.
In addition to membrane prostacyclin receptor signaling, there
may be additional prostacyclin ligand binding to nuclear receptors like peroxisome proliferator-activated receptor 
(PPAR ) (22, 23). Should lung vascular cells utilize prostacyclin nuclear receptors (such as PPAR ), then we would expect that signaling through this mechanism is not altered in our current model of membrane PGI2 receptor knockout mice.
If nuclear PGI2 receptor-dependent signaling also results in
inhibition of lung vascular remodeling, then our data in the
PGI-R KO mice could underestimate the total impact of PGI2
on hypoxia-induced pulmonary vascular remodeling.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Mark W. Geraci, M.D., Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center Campus Box C-272, 4200 E. Ninth Avenue, Denver, CO 80262. E-mail: mark.geraci{at}uchsc.edu
(Received in original form October 27, 2000 and in revised form March 23, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The authors thank Dr. Takayuki Maruyama and Dr. Kigen Kondo, Discovery Research Laboratories I, Minase Research Institute, Ono Pharmaceutical Co. LTD., for providing the PGI-R KO animals, and Dr. Rubin M. Tuder and Dr. Carlyne D. Cool, Department of Pathology, University of Colorado Health Sciences Center, for helpful discussion.
This work has been supported by NHLBI HL-43180 (N.F.V., M.W.G.) and the Shirley K. Wisham Memorial Research Foundaton for Pulmonary Hypertension Research.
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References |
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METHODS
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |