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BOR - Papers in Press, published online ahead of print December 17, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.024943
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BIOLOGY OF REPRODUCTION 70, 1171–1177 (2004)
DOI: 10.1095/biolreprod.103.024943
© 2004 by the Society for the Study of Reproduction, Inc.

Pregnancy

Calcium Homeostasis and Contraction of the Uterine Artery: Effect of Pregnancy and Chronic Hypoxia1

DaLiao Xiao, and Lubo Zhang2

Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California 92350


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The present study tested the hypothesis that chronic hypoxia alters pregnancy-mediated adaptation of Ca2+ homeostasis and contractility in the uterine artery. Uterine arteries were isolated from nonpregnant and near-term pregnant ewes of normoxic control or high-altitude (3820 m) hypoxic (oxygen pressure in the blood [PaO2], 60 mm Hg) treatment for 110 days. Contractions and intracellular-free Ca2+ concentration ([Ca2+]i) were measured simultaneously in the same tissue. In normoxic animals, pregnancy increased norepinephrine (NE), but not 5-hydroxy-thymide (5-HT) or KCl, contractile sensitivity in the uterine artery. Chronic hypoxia significantly attenuated NE-induced contractions in the pregnant, but not nonpregnant, uterine arteries. Similarly, 5-HT-mediated contractions of nonpregnant arteries were not changed. In the pregnant uterine artery, chronic hypoxia significantly increased NE-mediated Ca2+ mobilization, but decreased the Ca2+ sensitivity. In addition, hypoxia increased the calcium ionophore A23187-induced relaxation in pregnant, but not nonpregnant, uterine arteries. However, the A23187-mediated reduction of [Ca2+]i was significantly impaired in hypoxic arteries. In contrast, hypoxia significantly increased the slope of the [Ca2+]i-tension relationship of A23187-induced reductions in [Ca2+]i and tension in the pregnant uterine artery. The results suggest that the contractility of nonpregnant uterine artery is insensitive to moderate chronic hypoxia, but the adaptation of sympathetic tone that normally occurs in the uterine artery during pregnancy is inhibited by chronic hypoxia. In addition, changes in Ca2+ sensitivity of myofilaments play a predominant role in the adaptation of uterine artery contractility to pregnancy and chronic hypoxia.

calcium, catecholamines, environment, nitric oxide, pregnancy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pregnancy is associated with physiological changes in the maternal cardiovascular system that ensure normal fetal development. The development of the uteroplacental circulation accommodates a more than 20-fold increase in uterine blood flow in near-term pregnant sheep and in humans. Regulation of uterine blood flow during pregnancy is important not only for the growth and survival of the fetus, but also for cardiovascular well-being of the mother. Chronic hypoxia during the course of pregnancy is one of the most common insults to the maternal cardiovascular system and fetal development and is thought to be associated with increased risk of preeclampsia and fetal intrauterine growth restriction [1–4]. Previous studies have demonstrated that chronic hypoxia has profound effects on maternal uterine artery contractility [5–11]. In pregnant women residing at high altitude (3100 m) throughout pregnancy, uterine blood flow (milliliters per minute) at 36 weeks decreased, in comparison with those at low altitude (1600 m), owing primarily to a decreased vessel diameter resulting from a structural remodeling of the uterine artery [10]. In contrast, the blood flow velocity (centimeters per minute) was, in fact, higher in the high-altitude women, which in part helped to compensate for the reduced diameter and may have resulted from downstream vasodilation [10]. In the guinea pig, chronic high-altitude hypoxia did not diminish the pregnancy-associated reduction in contractile sensitivity to phenylephrine, but enhanced basal nitric oxide activity in the nonpregnant uterine artery and the pregnant mesenteric artery [8].

In pregnant sheep exposed to high-altitude (3820 m) hypoxia from Day 30 to approximately Day 140 of gestation, isolated uterine arteries exhibited decreased contractile response to a number of agonists such as norepinephrine (NE) and 5-hydroxy-thymide (5-HT), and enhanced the endothelium-dependent relaxation to calcium ionophore A23187 in precontracted vessels [5, 7, 12]. These changes were associated with decreased agonist-mediated pharmacomechanical coupling and increased endothelial nitric oxide synthase (eNOS) protein expression in the uterine artery [6, 7, 12]. In the present study, we tested the hypothesis that chronic hypoxia affected agonist-mediated intracellular Ca2+ and contractile responses differentially in the uterine arteries of nonpregnant and pregnant animals, and inhibits pregnancy-induced adaptation of Ca2+ homeostasis and contractility of the uterine artery. Agonist-mediated Ca2+ mobilization and contraction/relaxation responses were determined in uterine arteries obtained from nonpregnant and near-term pregnant ewes of normoxic control or high-altitude (3820 m) hypoxic (oxygen pressure in the blood [PaO2], 60 mm Hg) treatment for 110 days. By measuring the tension and intracellular-free Ca2+ concentration ([Ca2+]i) simultaneously in the same tissue, we were able to determine a contractile tension at a given [Ca2+]i and examine the effect of chronic hypoxia on apparent Ca2+ sensitivity (tension/[Ca2+]i) of myofilaments in the uterine arteries. Our results suggest that chronic hypoxia selectively regulates Ca2+ homeostasis in the pregnant uterine artery and inhibits pregnancy-enhanced Ca2+ sensitivity of myofilaments, leading to a decrease in contraction and an increase in relaxation at a given [Ca2+]i.


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

As previously described [5, 6, 12], nonpregnant and time-dated pregnant sheep were obtained from Nebeker Ranch in Lancaster, CA (altitude ~300 m; arterial PaO2 102 ± 2 mm Hg). Uterine arteries were obtained from nonpregnant and near-term (~140 days of gestation) pregnant sheep. For chronic hypoxia, nonpregnant and pregnant (30 days of gestation) animals were transported to Barcroft Laboratory, White Mountain Research Station, Bishop, CA (altitude, 3820 m; PaO2, 60 ± 2 mm Hg) and kept there for ~110 days. The animals were transported to the laboratory immediately before the studies. Ewes were anesthetized with thiamylal (10 mg/kg) administered via the external left jugular vein. The animals were then intubated, and anesthesia was maintained on 1.5%–2.0% halothane in oxygen throughout surgery. An incision in the abdomen was made and the uterus exposed. The uterine arteries were isolated, removed without stretching, placed into a modified Krebs solution (pH 7.4) of the following composition: 115.21 mM NaCl, 4.7 mM KCl, 1.80 mM CaCl2, 1.16 mM MgSO4, 1.18 mM KH2PO4, 22.14 mM NaHCO3, and 7.88 mM dextrose. EDTA (0.03 mM) was added to suppress oxidation of amines. The Krebs solution was oxygenated with a mixture of oxygen-carbon dioxide (95%:5%). After removal of the tissues, animals were killed with T-61 (euthanasia solution, Hoechst-Roussel, Somerville, NJ). All procedures and protocols used in the present study were approved by the Animal Research Committee of Loma Linda University and followed the guidelines by the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Simultaneous Measurement of [Ca2+]i and Tension

The third (nonpregnant) and fourth (pregnant) branches of the main uterine arteries with a similar external diameter were separated from the surrounding tissue and were cut into rings 2 mm in length. Simultaneously, measurement of contractile tension and [Ca2+]i in the same tissue was conducted as described previously [11, 13, 14]. Briefly, the arterial rings were attached to an isometric force transducer in a 5-ml tissue bath mounted on an intracellular Ca2+ analyzer (model CAF-110, Jasco, Tokyo, Japan). The tissues were equilibrated in Krebs buffer under a resting tension of 0.5 g for 40 min, and loaded with 5 µM fura-2-acetoxymethyl ester (Molecular Probes, Eugene, OR) for 4 h in the presence of 0.02% Cremophor EL at 25°C. The tissues were then washed with Krebs solution at 37°C for 30 min to allow for hydrolysis of fura-2 ester groups by endogenous esterase. Contractile tension and fura-2 fluorescence were measured simultaneously at 37°C in the same tissue. Concentration-response curves were obtained by cumulative additions of the agonists in approximate one-half log increments. Absolute tension was measured for NE and percent response for 5-HT and KCl. Calcium ionophore A23187-induced relaxation was measured as percent phenylephrine (1 µM) response. The tissues were illuminated alternatively (125 Hz) at excitation wavelengths of 340 and 380 nM, respectively, by means of two monochromators in the light path of a 75-W xenon lamp. Fluorescence emission from the tissue was measured at 510 nM with a photomultiplier. The fluorescence intensity at each excitation wavelength (F340 and F380, respectively) and their ratio (Rf340/f380) were recorded with a time constant of 250 msec and stored with the force signal on a computer. At the end of the experiments, the maximum fluorescence ratio was determined in a phosphate-free, bicarbonate-free, 120-mM K+ and 5-mM Ca2+ salt solution containing 10 µM ionomycin and 100 M NE. The minimum fluorescence ratio was determined by adding 10 mM EGTA. [Ca2+]i was determined, as described by Grynkiewictz et al. [15], using the following formula: [Ca2+]i (nM) = Kd [(R - Rmin)/(Rmax - R)](Sf2/Sb2), where Kd (224 nM at 37°C) is the dissociation constant of fura-2 for Ca2+; R is the ratio of fluorescence of the sample at 340 nm to that at 380 nm; and Rmin and Rmax represent the ratios of fluorescence at the same wavelengths in the presence of zero and saturating Ca2+, respectively; and Sf2/Sb2 is the ratio of fluorescence of fura-2 at 380 nm in zero Ca2+ to that in saturating Ca2+.

Data Analysis

Concentration-response curves were analyzed by computer-assisted nonlinear regression to fit the data using GraphPad Prism (GraphPad Software, San Diego, CA) to obtain the values of pD2 (-log EC50) and the maximum response. Results were expressed as means ± SEM, and the differences were evaluated for statistical significance (P < 0.05) by ANOVA.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Norepinephrine-Induced [Ca2+]i and Contractions

NE-induced, dose-dependent contractions of the uterine arteries from normoxic control and chronic hypoxic nonpregnant and pregnant animals are illustrated in Figure 1. In normoxic animals, there was a significant increase in the sensitivity (pD2) and the maximal response (Emax) of NE-induced contractions in the pregnant uterine artery (pD2, 6.92 ± 0.08; Emax, 5.17 ± 0.14 g) compared with those in the nonpregnant uterine artery (pD2, 6.46 ± 0.06; Emax, 2.44 ± 0.06 g; P < 0.05). Chronic hypoxia significantly attenuated NE-induced contractions in the pregnant uterine artery and decreased the pD2 from 6.92 ± 0.08 to 6.29 ± 0.08 (P < 0.05) and the Emax from 5.17 ± 0.14 g to 4.13 ± 0.16 g (P < 0.05). In contrast, chronic hypoxia had no effect on NE-induced contractions in the nonpregnant uterine artery (Fig. 1).



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  		FIG. 1. Cumulative concentration-response curves of NE-induced Ca2+ mobilization and contractions were obtained in nonpregnant and pregnant uterine arteries from normoxic (control) and chronic hypoxic (hypoxia) animals. Data are means ± SEM of tissues from five to six animals. The values of pD2 and the maximal response were presented in the text

NE-stimulated, dose-dependent increases in [Ca2+]i and the [Ca2+]i-tension relationship, depicted from the data of simultaneous measurement of [Ca2+]i and tension in the same tissue, are illustrated in Figures 1 and 2. Consistent with the results of contractions, chronic hypoxia did not affect NE-induced [Ca2+]i (pD2, 7.04 ± 0.16 vs. 6.79 ± 0.11; Emax, 287.4 ± 8.23 nM vs. 342.4 ± 9.99 nM; P > 0.05; Fig. 1) nor its [Ca2+]i-tension relationship (slope, 0.012 ± 0.002 g tension/nM vs. 0.013 ± 0.0009 g tension/nM [Ca2+]i; P > 0.05; Fig. 2) in the nonpregnant uterine artery. In the pregnant uterine artery, however, there was a significant decrease in the pD2 of NE-stimulated [Ca2+]i in the hypoxic tissues (6.34 ± 0.13) as compared with that in normoxic ones (7.14 ± 0.11; P < 0.05). In contrast, there was a significant increase in the maximal response from 283.9 ± 5.3 nM in normoxic to 522.4 ± 26.9 nM in hypoxic uterine arteries (P < 0.05; Fig. 1). In addition, chronic hypoxia caused a significant change in the [Ca2+]i-tension relationship in the pregnant uterine artery and decreased the slope from 0.0255 ± 0.0011 g tension/nM [Ca2+]i in normoxic tissues to 0.0093 ± 0.0003 g tension/nM [Ca2+]i in hypoxic ones (P < 0.05; Fig. 2).



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  		FIG. 2. NE-stimulated [Ca2+]i-tension relationship was determined by simultaneous measurement of [Ca2+]i and tension in the same tissue of nonpregnant and pregnant uterine arteries from normoxic (control) and chronic hypoxic (hypoxia) animals. Data are means ± SEM of tissues from five to six animals. The slope values were presented in the text

5-HT- and KCl-Induced [Ca2+]i and Contractions

Unlike NE-induced contractions, 5-HT- and KCl-stimulated [Ca2+]i and contractions were the same between nonpregnant and pregnant uterine arteries (Fig. 3). We have previously demonstrated that chronic hypoxia has no effect on KCl-mediated [Ca2+]i and contractions, but significantly inhibits 5-HT-induced [Ca2+]i and contractions in the pregnant uterine artery [11]. In contrast, chronic hypoxia had no effect on 5-HT-stimulated [Ca2+]i (pD2, 7.1 ± 0.1 vs. 7.3 ± 0.1; P > 0.05) and contractions (pD2, 7.0 ± 0.2 vs. 6.8 ± 0.1; P > 0.05) in the nonpregnant uterine artery.



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  		FIG. 3. Cumulative concentration-response curves of 5-HT- and KCl-induced increases in [Ca2+]i and contractions were obtained in nonpregnant and pregnant uterine arteries from normoxic animals. Data are means ± SEM of tissues from three to four animals

Calcium Ionophore A23187-Induced Relaxation and Decrease in [Ca2+]i

Calcium ionophore A23187 produced dose-dependent relaxations of both nonpregnant and pregnant uterine arteries precontracted with 1 µM phenylephrine (Fig. 4). Removal of endothelial cells abolished A23187-induced relaxations (data not shown). Chronic hypoxia significantly increased A23187-induced relaxation of the pregnant uterine artery, but had no effect on the relaxation in the nonpregnant artery (Fig. 4). Consistent with the relaxation, A23187 evoked concentration-dependent reductions of [Ca2+]i in both nonpregnant and pregnant uterine arteries precontracted with phenylephrine (Fig. 4). Chronic hypoxia had no effect on A23187-induced reduction of [Ca2+]i in the nonpregnant uterine artery, but significantly attenuated the A23187-mediated responses in the pregnant artery (Fig. 4). Simultaneous measurement of A23187-induced relaxation and reduction of [Ca2+]i in the same tissue indicated that chronic hypoxia significantly increased relaxation at a given reduction of [Ca2+]i (the slope: 1.35 ± 0.11 vs. 0.87 ± 0.07 %decreased tension/%decreased [Ca2+]i; P < 0.05) in the pregnant uterine artery (Fig. 5). In contrast, the slope of the A23187-mediated [Ca2+]i reduction and relaxation relationship in the nonpregnant uterine artery was the same between the normoxic (0.89 ± 0.01) and hypoxic (1.08 ± 0.05) animals (P > 0.05; Fig. 5).



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  		FIG. 4. Cumulative concentration-response curves of A23187-induced reduction of [Ca2+]i and relaxation were obtained in phenylephrine (PE, 1 µM) precontracted nonpregnant and pregnant uterine arteries from normoxic (control) and chronic hypoxic (hypoxia) animals. Data are means ± SEM of tissues from four to five animals and were analyzed by two-way ANOVA with A23187 as one factor and hypoxia as the other. *P < 0.05, hypoxia vs. control



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  		FIG. 5. A23187-mediated [Ca2+]i reduction and relaxation relationship was determined by simultaneous measurement of [Ca2+]i and tension in the same tissue of nonpregnant and pregnant uterine arteries from normoxic (control) and chronic hypoxic (hypoxia) animals. The slope values were presented in the text


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study has demonstrated that chronic hypoxia selectively regulates Ca2+ homeostasis in the pregnant uterine artery and inhibits pregnancy-enhanced Ca2+ sensitivity of myofilaments, leading to a decrease in contractions and an increase in relaxation at a given intracellular Ca2+ concentration.

In normoxic ewes, the present study demonstrated that pregnancy was associated with an increase in contractile sensitivity and the maximal response of NE-induced contractions in the uterine artery. The finding that neither 5-HT- nor KCl-induced Ca2+ mobilization and contractions were different between nonpregnant and pregnant uterine arteries suggests that the pregnancy-associated change in uterine artery contractility is selective to {alpha}-adrenergic stimulation. The increased {alpha}-adrenergic-mediated contractions in the pregnant uterine artery are consistent with our previous results [13, 14] and those of others in sheep [16] and rats [17–19]. These results suggest that decreased vascular tone in the uterine artery in pregnancy is accompanied by an increase in vasoconstriction reserve and contractile capability to {alpha}-adrenergic stimulation. Previous studies demonstrated that pregnancy induced transient and reversible denervation of the mammalian uterus and uterine artery [20–24]. This sympathetic denervation was associated with a profound decrease in contractions of uterine smooth muscle to electric field stimulation in late pregnancy [20]. Whereas the decreased sympathetic innervation, combined with increased nitric oxide synthesis/release [25–27], maintains low uterine vascular tone in pregnancy, sympathetic denervation is likely to up-regulate the postsynaptic {alpha}-adrenergic pathway and increase nonsynaptic {alpha}-adrenergic-mediated contractions in the uterine artery. This is supported by our previous findings that the density of {alpha}1-adrenergic receptors was significantly higher in pregnant than nonpregnant uterine arteries [13].

We have previously demonstrated that long-term high-altitude hypoxia significantly suppresses NE- and 5-HT-induced, but not KCl-induced, contractions in the pregnant uterine artery [5–7, 11]. The present study demonstrated that neither NE- nor 5-HT-induced Ca2+ mobilization and contractions in the nonpregnant uterine artery were changed by chronic hypoxia. This suggests that compared with the pulmonary artery that is sensitive to chronic hypoxia [28, 29], the uterine artery in the nonpregnant state is relatively resistant to moderate chronic hypoxia. However, the pregnancy-induced adaptation of the uterine artery is likely to be vulnerable to chronic hypoxia during the course of pregnancy. In the present study, when the pregnant animals were exposed to high-altitude hypoxia for about 80% of the gestational period, the contractile sensitivity of NE-induced contractions in the uterine artery was significantly decreased (pD2, 6.29) so that it became like a nonpregnant vessel (pD2, 6.46). This suggests that chronic hypoxia during pregnancy may inhibit pregnancy-induced changes of the uterine artery in response to {alpha}-adrenergic stimulation. This is supported by the findings that NE-mediated Ca2+ sensitivity was decreased in the hypoxic pregnant uterine artery (slope of 0.01), which was not different from that in the nonpregnant vessel (slope of 0.01). Studies in humans and guinea pigs suggested that chronic hypoxia for the entire gestation inhibited the normal remodeling that occurred in the uterine artery during pregnancy [10, 30]. The decreased contractile sensitivity of NE-induced contractions in isolated pregnant uterine arteries from the animals that had been exposed to chronic hypoxia for the most part of gestation, as compared with that in normoxic control pregnant animals, suggests that chronic hypoxia may inhibit sympathetic denervation that normally occurs in the uterine artery during pregnancy. This is supported by the previous findings in the same animal model that the density of postsynaptic {alpha}1-adrenergic receptors was significantly lower in the uterine artery from the animals exposed to chronic hypoxia during pregnancy than that in normoxic control pregnant uterine arteries [5]. Human and animal studies demonstrated that chronic hypoxia caused market activation of the sympathetic nervous system [9, 31–33]. Increased sympathetic tone in the uterine artery caused by chronic hypoxia during pregnancy may lead to a decrease in uterine blood flow. Although uterine blood flow was not measured in the present study, in pregnant women residing at high altitude (3100 m) throughout pregnancy, uterine blood flow at 36 weeks was decreased in comparison with those at low altitude [10].

The finding that NE-induced [Ca2+]i was increased in the pregnant uterine artery from the hypoxic animals is intriguing and suggests a differential adaptation of {alpha}1-adrenergic-mediated Ca2+ mobilization and Ca2+ sensitivity in the uterine artery to chronic hypoxia during pregnancy. We have previously demonstrated in the same animal model that chronic hypoxia during pregnancy decreases NE-mediated synthesis of inositol 1,4,5-triphosphate (IP3) in the uterine artery [6]. IP3 plays a key role in signal transduction, and the release of intracellular Ca2+ by IP3 has been implicated in many cellular responses mediated by hormones and neurotransmitters [34–36]. Taken together, the present results would suggest that either non-IP3-mediated Ca2+ mobilization or the IP3 sensitivity in Ca2+ release, or both, were increased in the pregnant uterine artery in the hypoxic animals. In the present study, despite the increase in NE-stimulated Ca2+ mobilization, the NE-induced contraction was decreased in the uterine artery in the animals exposed to chronic hypoxia during pregnancy compared with that in normoxic pregnant animals. This suggests that the decrease in Ca2+ sensitivity observed plays a predominant role in the adaptation of uterine artery contractility in the pregnant animals in response to chronic hypoxia. This is in agreement with our previous studies, demonstrating that changes in Ca2+ sensitivity dominate changes in uterine artery contractility during pregnancy [13].

Consistent with the results of agonist-induced contractions, the present study demonstrated that A23187-mediated relaxations of the nonpregnant uterine artery were the same between normoxic control and hypoxic animals. This further supports the relative insensitivity of the nonpregnant uterine artery to moderate chronic hypoxia. Careful analysis of the data reported by White et al. [8] indicated similar findings in guinea pigs in which chronic high-altitude hypoxia enhanced basal NO activity in the pregnant uterine artery, but not in the nonpregnant uterine artery. Since chronic hypoxia may inhibit pregnancy-induced sympathetic denervation in the uterine artery, as discussed above, the increased endothelium-dependent relaxation in the uterine artery in the animals exposed to chronic hypoxia during pregnancy may present a compensatory mechanism, counteracting the partly increased sympathetic tone in the pregnant uterine artery in hypoxic animals compared with that in normoxic pregnant animals. Our previous study has demonstrated that chronic hypoxia has no effect on eNOS protein levels in the nonpregnant uterine artery, but significantly increases eNOS in the pregnant vessel [12]. The present finding that the A23187-induced, endogenous NO-mediated decrease in [Ca2+]i in uterine artery smooth muscle is consistent with previous studies, showing an obligatory role of Ca2+ reduction in the A23187-mediated relaxation [37–43]. In the pregnant uterine artery, in contrast to the increased A23187-induced relaxations, A23187-mediated reduction in [Ca2+]i was decreased in the hypoxic animals. The simultaneous measurement of the A23187-induced decrease in [Ca2+]i and relaxation indicated a decrease in Ca2+ sensitivity of myofilaments (i.e., an increased relaxation at a given [Ca2+]i) in hypoxic pregnant uterine arteries. This is consistent with the results of contractions (i.e., a decrease in Ca2+ sensitivity of myofilaments in the uterine artery in the animals exposed to chronic hypoxia during pregnancy leads to a decrease in contraction and an increase in relaxation at a given intracellular Ca2+ concentration).

In summary, the major findings of the present studies are 1) pregnancy selectively increased contractile sensitivity and the maximal response of NE-induced contractions in the uterine artery, which is associated with an increased NE-mediated Ca2+ sensitivity of myofilaments; 2) chronic hypoxia during pregnancy suppresses the pregnancy-associated increase in the NE-induced contractions so that it becomes like a nonpregnant vessel; 3) chronic hypoxia differentially regulates Ca2+ homeostasis in the pregnant uterine artery by decreasing NE-mediated Ca2+ sensitivity, but increasing NE-induced Ca2+ mobilization; 4) chronic hypoxia enhances a pregnancy-induced increase in endothelium-dependent relaxation in the uterine artery, which is associated with a reduction in Ca2+ sensitivity of myofilaments; and 5) chronic hypoxia has no effect on NE-induced Ca2+ mobilization and contractions, nor on endothelium-dependent relaxations in the nonpregnant uterine artery. These results suggest that 1) the contractility of the uterine artery in the nonpregnant state is insensitive to moderate chronic hypoxia, 2) chronic hypoxia inhibits sympathetic denervation that normally occurs in the uterine artery during pregnancy, and 3) changes in Ca2+ sensitivity of myofilaments play a predominant role in the adaptation of uterine artery contractility to pregnancy and chronic hypoxia. The potential interaction of pregnancy with chronic hypoxia in the regulation of steroid hormones and their effects on uterine artery contractility presents an intriguing avenue for future investigation.


   FOOTNOTES
 
1 Supported in part by NIH grants HL-57787, HL-67745, and HD-31226, and by Loma Linda University School of Medicine. Back

2 Correspondence: Lubo Zhang, Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350. FAX: 909 558 4029; lzhang{at}som.llu.edu Back

Received: 30 October 2003.

First decision: 7 December 2003.

Accepted: 9 December 2003.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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