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J Appl Physiol 90: 2502-2507, 2001;
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Vol. 90, Issue 6, 2502-2507, June 2001

HIGHLIGHTED TOPICS
Physiological and Genomic Consequences of Intermittent Hypoxia
Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia

Karen A. Fagan

Cardiovascular Pulmonary Research Laboratory, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Sleep apnea (intermittent periods of hypoxia with or without hypercapnia) is associated with systemic hypertension and increased mortality from cardiovascular disease, but the relationship to pulmonary hypertension is uncertain. Previous studies on intermittent hypoxia (IH) in rats that demonstrated pulmonary hypertension utilized relatively long periods of hypoxia. Recent studies that utilized brief periods of hypoxia have conflicting reports of right ventricular (RV) hypertrophy. In addition, many studies have not measured pulmonary hemodynamics to asses the severity of pulmonary hypertension in vivo. Given the increasing availability of genetically engineered mice and the need to establish a rodent model of IH-induced pulmonary hypertension, we studied the effect of IH (2-min cycles of 10% and 21% O2, 8 h/day, 4 wk) on wild-type mice, correlating in vivo measurements of pulmonary hypertension with RV mass and pulmonary vascular remodeling. RV systolic pressure was increased after IH (36 ± 0.9 mmHg) compared with normoxia (29.5 ± 0.6) but was lower than continuous hypoxia (44.2 ± 3.4). RV mass [RV-to-(left ventricle plus septum) ratio] correlated with pressure measurements (IH = 0.27 ± 0.02, normoxia = 0.22 ± 0.01, and continuous hypoxia = 0.34 ± 0.01). Hematocrits were also elevated after IH and continuous hypoxia (56 ± 1.6 and 54 ± 1.1 vs. 44.3 ± 0.5%). Evidence of neomuscularization of the distal pulmonary circulation was found after IH and continuous hypoxia. We conclude that mice develop pulmonary hypertension following IH, representing a possible animal model of pulmonary hypertension in response to the repetitive hypoxia-reoxygenation of sleep apnea.

sleep apnea; vascular remodeling; polycythemia


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

SLEEP APNEA IS A COMMON SYNDROME manifested by repeated cycles of hypoxia and reoxygenation with or without hypercapnia affecting an estimated 2-4% of adults in the United States. Sleep apnea is associated with systemic hypertension, altered systemic vasoreactivity, and increased cardiovascular mortality, but the association between sleep apnea and pulmonary hypertension is less certain (22, 23, 29, 47, 48). The incidence of pulmonary hypertension in sleep apnea is thought to be low (15%) and associated with concomitant lung disease or daytime hypoxemia (6, 7, 28, 53, 44). Recently, mild daytime pulmonary hypertension was found in 30-40% of patients with sleep apnea without lung disease and was associated with increased hypoxia-induced pulmonary vasoconstriction (44, 45). Although these observations suggest a relationship between pulmonary hypertension and repetitive hypoxia-reoxygenation, no carefully defined rodent model of intermittent hypoxia-induced pulmonary hypertension presently exists.

In animals exposed to intermittent hypoxia-reoxygenation cycles simulating sleep apnea, systemic hypertension is common and may be due to sympathetic activation (1, 11, 13, 15, 16, 18). However, conflicting findings regarding the development of pulmonary hypertension have been reported. Rats developed pulmonary hypertension [right ventricular (RV) hypertrophy, increased right ventricular pressure, polycythemia, and pulmonary vascular remodeling] when exposed to 8- to 30-min hypoxic periods (total of 4 h) or at least 2 h of continuous hypoxia per 24 h (27, 35, 37-39, 41, 42). However, the duration of hypoxemia in these experiments is longer than typically seen in sleep apnea. In studies with shorter hypoxia-reoxygenation cycles (30-90 s/min, 8 h/day, for several weeks), rats have increased (1, 13, 14, 16, 30, 34) or unchanged (1, 12, 14, 16) RV mass. However, these recent reports have not confirmed the presence of pulmonary hypertension with in vivo measurements of RV pressure.

Continuous hypoxia leads to development of significant pulmonary hypertension, RV hypertrophy, polycythemia, and pulmonary vascular remodeling in mice (9, 20, 50). However, it is not known whether mice develop pulmonary hypertension as a result of intermittent hypoxia. This study addresses the development of pulmonary hypertension following intermittent hypoxia in mice. With the growing availability of transgenic mice, development of a murine model will help identify mechanisms leading to pulmonary vascular disease following intermittent hypoxia similar to that seen in sleep apnea.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Mice. Male CB57BL/6J mice (Jackson Laboratory), 6 wk of age, were allowed to acclimatize for 2 wk after arrival and before experimentation. Cages were changed twice per week. Mice had free access to water and food throughout the experiments.

Hypoxia exposure. Mice were housed under one of three experimental conditions: normoxia (Denver, CO), hypoxia (hypobaric chamber at 17,000-ft elevation), or intermittent hypoxia for 4 wk. All cages were of the same size and dimensions, and equal numbers of mice were in each cage. Normoxic and hypoxic exposures were continuous for 24 h/day. Intermittent hypoxia exposure was as follows. Standard cages were sealed with a Plexiglas lid with two holes, one for water bottle access and one for O2 monitoring. One hole was placed in both the front and rear of the cage for directional flow of gas. Compressed air (21% O2) and hypoxic gas (10% O2, balance N2) were connected to a pinch-valve switch and set with regulators to deliver either gas at a constant pressure of 5 psi through the inflow to the cage. Timers for the switch were set at 2 min, and O2 was continuously monitored at the rear of the cage. Flow was therefore directional through the cage. A fan was not used to disperse the gas at the inflow because O2 measured in multiple areas of the cage was similar. Animals were exposed to 2-min cycles of compressed air or hypoxic gas beginning at 9:00 AM and ending at 5:00 PM each day for 28 days to coincide with sleep cycle. During other times, animals were exposed to room air.

In vivo hemodynamic measurements. Right ventricular systolic pressure (RVSP, mmHg) was measured as previously described. (9) Briefly, mice were anesthetized with ketamine and xylazine (100 and 15 mg/kg, respectively) and placed supine while spontaneously breathing room air; a 26-gauge needle was introduced percutaneously into the thorax via a subxiphoid approach. RVSP was verified in real time and recorded. Blood was withdrawn, and animals were killed. Animals from continuous-hypoxia exposure were kept hypoxic until immediately before hemodynamic measurement. Intermittently hypoxic animals were studied immediately after they were removed from at least a 4-h intermittent hypoxia exposure on the day of experimentation.

Measurements of RV mass. Immediately after death, the heart was resected and the atria were removed at the plane of the atrioventricular valves. The RV free wall was then dissected free of the left ventricle (LV) and septum (S). The RV and LV plus S were weighed (g), and the RV-to-(LV + S) ratio was calculated.

Hematocrit measurements. Blood was collected by direct cardiac puncture immediately before death into a heparinized syringe; 100 µl of heparinized blood were placed in capillary tubes, and hematocrit (%) was determined by standard techniques.

Immunohistochemistry. Lungs from experimental animals were obtained after we measured the closed chest pressure, and physiological buffered saline was perfused through the pulmonary circulation to remove red blood cells. Lungs were then inflated with 1% agarose, fixed in methycarnoys (60% methanol, 30% chloroform, and 10% glacial acetic acid), embedded in paraffin, and sectioned. Sections were stained with anti-myosin antibodies (1:1,000, BassM) and counterstained with hematoxylin. Ten fields (×20) were studied per animal, and the number of myosin-positive small vessels per field was determined. Images were viewed with Zeiss Axioskop and photographed with Zeiss AxioCam digital system.

Statistical analysis. All results are reported as means ± SE. Significance was determined with P <=  0.05 using one- and two-way ANOVA with Fisher's post hoc tests.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Inspired PO2 during intermittent hypoxia. As shown in Fig. 1, flushing cages with compressed normoxic air (21% O2) or hypoxic gas (10% O2) resulted in brisk fluctuations of inspired PO2 from ~122 to ~58 Torr.


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  		Fig. 1.   Inspired PO2 (PIO2) measured at rear of cage demonstrating rapid cycling between ~122 and 58 Torr every 2 min.

Pulmonary hypertension following intermittent hypoxia. Mice exposed to either continuous or intermittent hypoxia had significant increases in RVSP compared with normoxic mice. (Fig. 2). RVSP was higher in continuously hypoxic than in intermittently hypoxic mice.


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  		Fig. 2.   Right ventricular systolic pressure (RVP; mmHg) as an estimate of pulmonary artery pressure in normoxic (n = 6), intermittently hypoxic (Intermitt; n = 5), and continuously hypoxic mice (n = 6). *P < 0.05 compared with continuous group; **P < 0.05 compared with intermittent group; ***P < 0.05 compared with continuous group.

RV hypertrophy following intermittent hypoxia. Consistent with the RVSP measurements, mice exposed to either continuous or intermittent hypoxia had increased RV mass compared with normoxic mice. The RV hypertrophy was greater in continuously hypoxic than intermittently hypoxic mice. (Fig. 3). RV per body weight measurements were consistent with the RV/LV + S (data not shown). There was no difference in LV per body weight among the groups (normoxic = 0.322 ± 0.011, intermittent hypoxia = 0.328 ± 0.009, and continuous hypoxia = 0.336 ± 0.01 mg/g; P = not significant).


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  		Fig. 3.   Right ventricular (RV) mass [RV-to-left ventricle + septum ratio (RV/LV + S)] in normoxic (n = 6), intermittently hypoxic (n = 5), and continuously hypoxic mice (n = 6). *P < 0.05 compared with normoxic and intermittent groups; **P < 0.05 compared with intermittent group.

Polycythemia following intermittent hypoxia. As shown in Fig. 4, mice exposed to either continuous or intermittent hypoxia developed significant polycythemia compared with normoxic mice.


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  		Fig. 4.   Hematocrits (Hct; %) in normoxic (n = 6), intermittently hypoxic (n = 5), and continuously hypoxic mice (n = 6). *P < 0.05 compared with intermittent and continuous groups. ns, Not significant.

Vascular remodeling following intermittent hypoxia. Lungs of mice exposed to continuous or intermittent hypoxia had significantly increased numbers of muscularized small pulmonary vessels (myosin-positive staining) per high-powered field compared with normoxic mice. (Fig. 5A, a and b) There was a tendency for the numbers of muscularized vessels to be greater in continuously hypoxic than intermittently hypoxic lungs.


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  		Fig. 5.   A: representative myosin staining of peripheral lung and small vessels in normoxic (a), intermittently hypoxic (b), and continuously hypoxic (c) mice. Dark brown/black staining indicated with arrows is myosin positive. In a, vessel is a bronchial artery (not counted but shown as positive) and second arrow highlights airway smooth muscle cell. B: number of myosin-positive vessels per high-powered field (HPF) in normoxic, intermittently hypoxic, and continuously hypoxic mice. *P < 0.005 compared with intermittent and continuous groups.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

This is the first report of pulmonary hypertension in mice in response to intermittent hypoxia that simulated the rapid hypoxia-reoxygenation cycles of sleep apnea. Previous reports of increased RV mass in rats after exposure to intermittent hypoxia are conflicting and have not included measurements of hemodynamics in vivo to confirm the presence of pulmonary hypertension or directly compared the findings in intermittent vs. continuous hypoxia (1, 13, 16, 30, 34). In the present study, the development of pulmonary hypertension in intermittently hypoxic mice was confirmed by in vivo measurements of RVSP and the presence of pulmonary vascular muscularization and RV hypertrophy.

Because continuous hypoxia was found to cause pulmonary hypertension in mice (9, 20, 49) and previous reports suggested the possibility of pulmonary hypertension in rats following intermittent hypoxia (1, 13, 14, 16, 30, 34), the finding of pulmonary hypertension in mice as a result of intermittent hypoxia was not entirely surprising. In humans, acute increases in pulmonary arterial pressure are associated with nocturnal hypoxemic episodes and may lead to the development of pulmonary hypertension (6, 33, 44). Indeed, patients with sleep apnea and resting daytime pulmonary hypertension have increased hypoxic pulmonary vasoconstriction as well as increased resistance to pulmonary blood flow, suggesting both a reactive and fixed (remodeled) vascular component of the pulmonary hypertension (45). Thus mice with intermittent hypoxia-induced pulmonary hypertension may model pulmonary vascular disease associated with the repetitive hypoxic episodes of sleep apnea.

Hypercapnia, along with hypoxia, is also often found in patients with sleep apnea. In the present report, the mice were not made hypercapnic, and, although we did not measure arterial blood gasses, the mice were likely hypocapnic. In rats, acute exposure to eucapnic intermittent hypoxia led to augmented blood pressure elevation compared with results shown with hypocapnic intermittent hypoxia (2, 12). However, chronic exposure to eucapnic or hypercapnic intermittent hypoxia did not lead to augmentation of systemic hypertension (11-13). Thus the effect of hypercapnia on the systemic circulation in intermittent hypoxia is not clear (11). The action of carbon dioxide in the pulmonary circulation may depend on the pulmonary arterial pressure with hypercapnia causing vasoconstriction at low pulmonary arterial pressure and vasodilation at high pressure (4, 5). Recently, hypercapnia was reported to decrease RV hypertrophy following continuous hypoxia (40), whereas chronic exposure to hypercapnic, but not eucapnic, intermittent hypoxia led to increased RV mass compared with hypocapnic intermittent hypoxia (12, 13). We therefore hypothesize that the addition of hypercapnia might have further augmented the development of pulmonary hypertension in mice in intermittent hypoxia and is under current investigation.

The expression of a variety of vasodilators (nitric oxide, PGI2), vasoconstrictors (endothelin-1), and growth factors (vascular endothelial growth factor) is altered in rats and mice exposed to continuous hypoxia (8, 32, 43, 51, 54). It is not known whether expression of factors regulating pulmonary vascular tone and structure is altered in mice exposed to intermittent hypoxia as occurs in mice exposed to continuous hypoxia. The use of genetically engineered mice has increased our understanding of the importance of endogenous vasodilators (9, 10, 17, 20) and vasoconstrictors (24) in the susceptibility to hypoxia-induced pulmonary hypertension. How these mediators may be important in the pulmonary hypertension in mice following intermittent hypoxia is not known but could be clarified in future studies with genetically engineered mice.

Polycythemia may lead to increased viscosity and pulmonary vascular resistance (3) and has been reported as increased (30, 34) or unchanged (1, 13) following intermittent hypoxia. However, excessive polycythemia is not common in patients with uncomplicated sleep apnea. (25) Thus pulmonary hypertension in sleep apnea cannot be completely accounted for by elevations in hematocrit. It has been previously reported that continuous hypoxia leads to increased hematocrit in mice (9, 50). Interestingly, in the present study, the severity of polycythemia was not different between intermittently and continuously hypoxic mice. In previous studies with rats, the severity of polycythemia following continuous hypoxia was not measured for comparison (13, 30, 34). Increased sympathetic tone following intermittent hypoxic may increase hematocrits by causing splenic contractions (31, 42). The polycythemia in the present report may also be due to the duration of hypoxia (4 h total per 24 h in 2-min cycles); previous studies identified that 2 h of continuous hypoxia or eight 30-min hypoxic exposures (4 h total) per 24 h were sufficient to raise red blood cell mass (37). Hypoxia may increase hematocrit by activation of transcription factor hypoxia-inducible factor (HIF)-1alpha , leading to increased production of erythropoietin. Lung HIF-1alpha expression is increased following continuous hypoxia, and mice partially deficient in HIF-1alpha have a decreased polycythemic response to hypoxia (52, 55, 56). However, the expression of HIF-1alpha following intermittent hypoxia is unknown. Changes in redox state due to repetitive hypoxia-reoxygenation in intermittent hypoxia may also stimulate expression of transcription factors (including activator protein-1 and HIF-1alpha ) important in regulating expression of a variety of genes that are important in the development of pulmonary hypertension (19, 46).

Although systemic hypertension as a result of intermittent hypoxia is common in rats, we did not observe an increase in LV mass, suggesting the absence of systemic hypertension (1, 11, 13, 16, 30). However, in the present study, measurements of systemic pressure were not performed to directly confirm the lack of systemic hypertension. Further studies are necessary to determine the susceptibility of the mouse compared with the rat or significant differences in strains of mouse to the development of systemic hypertension following intermittent hypoxia (21, 36).

Increased numbers of small pulmonary resistance vessels expressing myosin were found after exposure to intermittent hypoxia. This suggests that the pulmonary hypertension was at least partly due to vascular remodeling. The similarity in degree of muscularization of small pulmonary vessels found after continuous and intermittent hypoxia indicates that similar mechanisms for remodeling may have been involved. Previous reports in continuously hypoxic mice have also demonstrated neomuscularization of the distal pulmonary arteries (9, 20, 50). Previous reports of pulmonary vascular remodeling due to intermittent hypoxia in rats utilized longer periods of hypoxia (26, 27, 35, 41), suggesting that the duration of hypoxia may be important. The presence of hypercapnia may also be important in pulmonary vascular remodeling, as chronic hypercapnic hypoxia attenuated pulmonary vascular remodeling compared with chronic hypoxia in rats (40). The mechanisms by which pulmonary arteries remodel after intermittent hypoxia are not clear but may involve altered expression of mitogens for vascular smooth muscle, leading to remodeling similar to that in chronically hypoxic mice.

In summary, we have identified the presence of pulmonary hypertension using direct in vivo measurements of RV pressure and of pulmonary vascular remodeling and RV hypertrophy in mice exposed to repetitive periods of hypoxia. This represents the first description of a murine model of pulmonary hypertension following intermittent hypoxia and, with the growing availability of transgenic mice, may be useful in studies of pulmonary vascular diseases associated with intermittent hypoxia. Although the episodic nature of the hypoxia may be similar to that seen in sleep apnea, further studies utilizing hypercapnia are needed to more closely mimic sleep apnea in mice.


    ACKNOWLEDGEMENTS

I thank Leonard Latham for modification of animal cages and timed pinch-valve design and construction, Julie Wright Harral for assistance with immunohistochemistry, and Kenneth G. Morris, Jr., for assistance with hemodynamic measurements.


    FOOTNOTES

Address for reprint requests and other correspondence: K. A. Fagan, 4200 East Ninth Ave., B-133, Denver, CO 80262 (E-mail: karen.fagan{at}uchsc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1 February 2001; accepted in final form 2 March 2001.


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DISCUSSION
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J APPL PHYSIOL 90(6):2502-2507
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