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1 Perinatal Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; and 2 Maternal and Fetal Health Research Centre, University of Manchester, St. Mary's Hospital, Manchester M13 0JH, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The mechanisms underlying vascular
adaptations in pregnancy remain to be fully elucidated. One of the
contributory mechanisms for reduced vascular tone may be a reduction of
myogenic tone. Myogenic tone was assessed as the difference between
internal diameter in the presence and absence of external calcium at
different intramural pressure steps (60-100 mmHg). Myogenic
responses were reduced in resistance-sized mesenteric and main uterine
arteries in late pregnant compared with nonpregnant C57BL/6J mice. In
vessels from pregnant, but not nonpregnant mice, the myogenic response was enhanced by preincubation with nitric oxide (NO) synthase inhibitor
NG-nitro-L-arginine methyl ester,
was further elevated by the gap junction inhibitor 18-
glycyrrhetinic acid, but was unaltered by the prostaglandin H synthase
inhibitor meclofenamate. Endothelium removal enhanced myogenic
tone only in the vessels from pregnant animals, thus confirming the
role of the endothelium in modulating myogenic tone in pregnancy. These
results suggest that endothelium-derived NO as well as gap junction
communications modulate myogenic tone in mouse pregnancy.
vascular tone; endothelium; mesenteric arteries; uterine arteries
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NORMAL HUMAN PREGNANCY is associated with tremendous changes in the cardiovascular system that include an increase in the plasma volume and cardiac output. Despite this, blood pressure falls and reaches its nadir in the second trimester (16). The reduction in peripheral vascular resistance plays a major role in reducing blood pressure. Despite intense investigation, the pathways underlying this adaptation to pregnancy remain to be elucidated, and a deficient adaptation may be important in the pregnancy complication preeclampsia (28). Many contributory mechanisms have been suggested; one potential mechanism is a reduction of myogenic tone in pregnancy.
Myogenic tone, the intrinsic ability of a blood vessel to constrict in response to an increase in the intramural pressure, plays an important role in maintaining blood flow and is predominant in small arteries (1). Although the precise mechanism is unclear and likely to be very complex (40), myogenic tone exerts direct effects on smooth muscle and results in depolarization and increased intracellular Ca2+.
The data regarding the effect of pregnancy on myogenic tone are controversial and sometimes conflicting. Some studies have demonstrated reduced myogenic tone in mesenteric arteries (30) and small renal arteries (14) from pregnant rats. However, others (8, 24) have reported no change of myogenic tone in mesenteric arteries obtained from late pregnant rats. Results from these latter studies suggested that flow-induced dilation, mediated by nitric oxide (NO), may be involved in vasodilation of pregnancy rather than a reduction of myogenic tone
The role of NO in cardiovascular adaptive responses during pregnancy has been extensively studied but still is under debate (reviewed in Ref. 37). Pertinent to our current study, NO was previously shown to modulate myogenic tone in small renal arterioles of pregnant rats (14). In myometrial resistance arteries from pregnant women, NO modulated both myogenic tone and flow-mediated relaxation (23). Conversely, in small subcutaneous vessels from pregnant women, as well as mesenteric arteries from pregnant rats, NO modulates only flow-mediated relaxation (7, 8). Although evidence exists that NO plays a role in pregnancy-induced vasodilation of systemic and uterine arteries, discrepancies exist between studies, thus the role of NO in the modulation of myogenic tone is not fully understood.
Apart from NO, there may be other factors contributing to increased endothelium-dependent relaxation in pregnancy, such as gap junction communications. Gap junctions may allow, at least in part, both NO (18) and other hyperpolarizing factor(s) (2, 13, 15, 34) to pass from the endothelium to the vascular smooth muscle cells via heterocellular gap junctions (3, 18, 38). Gap junctions are membrane-localized channels that permit intercellular movement of small molecules, thus facilitating intercellular communication of cellular activities (4, 26). Gap junctions form between two cells when connexon hemichannels dock with each other. Each channel consists of six connexin protein subunits arranged around a central pore. Increased gap junction communications were shown in the uterus and the uterine, mesenteric, thoracic aortic arterial segments of pregnant rats (10). Furthermore, involvement of gap junction communication in NO and prostanoid-independent vasodilation has been recently shown in human small myometrial arteries from normal pregnant women (20). However, the role of gap junctions in modulation of myogenic tone in pregnancy is not known.
The evolution of inbred mouse strains and the recent advent of genetically manipulated mice are being used to gain a better understanding of specific pathways in a variety of syndromes including preeclampsia (12). However, there is a surprising paucity of information regarding normal pregnancy adaptations in mice. Therefore, the current study was performed to understand the normal physiological changes that occur to myogenic tone in pregnant mice. We have hypothesized that myogenic tone is reduced in pregnant mice due to endothelial (NO)-dependent mechanisms, and we also investigated whether increased gap junctional communication contributes to augmented endothelium-dependent modulation of myogenic tone in pregnancy.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals, breeding, and tissue collection. Six-month-old female C57BL/6J mice (Jackson Laboratories; Bar Harbor, ME) were used to perform the experiments. Mice were housed in polypropylene cages in groups of four in a temperature- and humidity-controlled environment. Animal-housing facilities were controlled on a 12 h-12 h light-dark cycle, and mice were given free access to standard laboratory chow and water. Late pregnant (16-18 days gestation, normal period of gestation 19 days) and nonpregnant mice were included in this study. After the mice were euthanized (cervical dislocation), mesentery and uterus were removed and placed immediately in freshly prepared cold Dulbecco's medium. Dulbecco's medium contained Dulbecco's modified Eagle medium base (Sigma) supplemented with (in mM) 1 sodium pyruvate, 25 sodium bicarbonate, 5 HEPES, and 5 glucose. We used Dulbecco's medium because this contains nutrient amino acids and vitamins that improved viability of vessels (27, 39).
One resistance-sized mesenteric and one main uterine arterial segment were obtained from each animal. We chose the mesenteric bed because it contributes substantially to vascular resistance in conscious rats (5), and pregnancy-induced alterations have previously been shown in isolated rat mesenteric arteries (11). The advantage of studying the uterine artery is that this artery undergoes the maximum changes in pregnancy, and failures of adaptation are known to occur in preeclampsia and intrauterine growth restriction. Second-order arteries were dissected of surrounding fat and mounted in a pressure myograph (Living Systems Instrumentation; Burlington, VT). Vessels were secured between two glass cannulas. The proximal cannula was connected to the pressure servounit, and the distal end was shut off with a stopcock. Dulbecco's medium was maintained at 37°C and at a pH 7.4 in a hot water bath and added to the baths of arterial chamber at 10-min intervals. Medium in dual-chamber arteriograph was maintained at 37°C with the aid of an built-in microprocessor temperature controller that works in conjunction with power supply. Minute fluctuations in temperature are detected with the help of a sensitive glass-encased chromel-alumel thermocouple probe inserted into the bath chambers, which are held by clamps alongside the mounted vessels. The vessels were imaged by using a video camera, and internal diameter and wall thickness were measured with a video dimension analyzer (17).Experimental protocols. After being mounted, blood vessels (small mesenteric and main uterine arteries) were equilibrated in warm (37°C) Dulbecco's medium for 30 min at an intraluminal pressure of 50 mmHg, prestretched by increasing intraluminal pressure from 50 to 75 mmHg, and then returned to 50 mmHg immediately (9). The vessels were then allowed to equilibrate at 50 mmHg for another 30 min.
After the equilibration process, the intraluminal pressure was reduced to 2 mmHg, and the vessels were further stabilized for 10 min. The pressure was then increased from 2 to 10 mmHg and in a stepwise manner from 10 to 100 mmHg in 10-mmHg increments. A diameter measurement was taken 5-6 min after each pressure step. This protocol for assessing myogenic tone was then repeated in the presence NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 µM). This dose of L-NAME was determined from preliminary studies that showed that NG-nitro-D-arginine methyl ester (control of drug for L-NAME) at a dose of 200 µM had vasoconstrictor effects in the pregnant vessels. Similarly, the prostaglandin H synthase (PGHS) inhibitor meclofenamate (1 µM) was also used to investigate prostaglandin pathway. The involvement of gap junctions in pregnancy was determined by using gap junction inhibitor 18- glycyrrhetinic acid (18- GA, 100 µM) (36). At
the end of each protocol, vessels were returned to 50 mmHg and
stabilized for 10 min. L-NAME and meclofenamate were
incubated for 20 min, and 18-GA was incubated for 30 min before
pressure steps were performed. Time-control experiments were performed
to ascertain the repeatability of vessel responses in both pregnant and
nonpregnant groups.
Myogenic tone was also assessed after removal of the endothelium.
Endothelium was denuded by injecting air bubbles through the vessels
while still mounted in the arterial chamber (volume of injected of air
bubbles ~0.3 ml) (21). Phenylephrine was used to elevate
tone by 50%, and methacholine (1.0 µM was used to test endothelium
integrity). Vessels were considered endothelium denuded when
methacholine reversal of phenylephrine induced tone was <10%. At the
conclusion of each experiment, passive curves were constructed in the
absence of extracellular Ca2+.
Calculations.
Because uterine diameters were different between pregnant mice compared
with nonpregnant mice (Table 1),
calculations were performed by using the following formula to calculate
percent myogenic tone at each pressure step: percent myogenic tone = (D1 
D2)/D1 × 100, where
D1 is the internal diameter in
Ca2+-free medium, and D2 is the
internal diameter in the presence of extracellular Ca2+.
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Data analysis. Data are expressed as means ± SE. Analysis of data was performed by using two-way repeated-measures ANOVA with post hoc Bonferroni's test for multiple comparisons. Mann-Whitney's rank sum test was used to compare arterial diameters in mesenteric and uterine arteries from nonpregnant and pregnant mice. Statistical significance was accepted at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of intraluminal pressure on vessel reactivity in
pregnancy.
Mesenteric and uterine arteries both developed myogenic tone under in
vitro conditions. Figure 1A
shows that stepwise increases in intraluminal pressure in the presence
of extracellular Ca2+, up to 60 mmHg, caused a sequential
increase in internal diameter in small mesenteric arteries from
nonpregnant mice. A subsequent increase in pressure thereafter resulted
in constriction of the vessel (the myogenic response). Figure 1,
A and B, also illustrates the dependence of
myogenic tone on Ca2+ influx in these vessels. Increasing
intraluminal pressure after removal of extracellular Ca2+
caused the vessels to dilate and abolished myogenic response. Myogenic
tone was significantly reduced in mesenteric arteries from pregnant
mice (n = 15, P < 0.001) compared with
nonpregnant mice (n = 16, Fig. 1C). A
similar reduction in myogenic tone was also noted in uterine arteries
from pregnant (n = 11, P = 0.035) compared with nonpregnant mice (n = 10, Fig.
2).
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Effect of NOS and PGHS inhibition on myogenic tone in pregnancy.
In mesenteric and uterine arteries from nonpregnant mice,
L-NAME alone, meclofenamate alone (data not shown), and
L-NAME and meclofenamate in combination had no effect on
myogenic tone (Fig. 3A and
4A).
However, in mesenteric arteries of pregnant mice, L-NAME
treatment significantly enhanced myogenic tone (P < 0.001, Fig. 3B), whereas meclofenamate alone (data not
shown) or in combination with L-NAME did not alter
myogenic tone (Fig. 3B).
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Effect of gap junction inhibition on myogenic tone in pregnancy.
The gap junction inhibitor 18- GA had no additional effect on
myogenic constriction above that caused by L-NAME and
meclofenamate in both mesenteric arteries from pregnant and nonpregnant
mice and uterine arteries from nonpregnant mice (Fig. 5,
A-C). However, in uterine
arteries from pregnant mice, 18- GA further enhanced myogenic tone
to a greater extent than L-NAME and meclofenamate (P = 0.029, Fig. 5D).
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Effect of endothelium removal on myogenic tone in pregnancy.
Removal of the endothelium enhanced basal tone and myogenic tone in
mesenteric arteries (P = 0.019, Fig.
6B) and uterine arteries (P = 0.041, Fig. 6D) from pregnant mice. In
contrast, endothelium removal affected only basal tone without
affecting myogenic tone (pressures > 60 mmHg) in mesenteric
arteries from nonpregnant mice (Fig. 6A). Removal of the
endothelium had no effect on basal or myogenic tone in uterine arteries
from nonpregnant animals (Fig. 6C).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Myogenic tone has an important role in the modulation of vascular resistance and blood flow to various organs; thus any alteration could potentially contribute to maladaptation of vascular hemodynamics in pregnancy. The results of the present study demonstrate that myogenic tone is reduced in small mesenteric and main uterine arteries from pregnant compared with nonpregnant animals, and this may contribute to reduced vascular tone in mouse pregnancy. The involvement of the endothelium in modulating myogenic tone was demonstrated as endothelial removal enhanced myogenic tone in vessels from pregnant animals. In addition, NO, an important endothelial-derived vasodilator, modulated myogenic tone only in arteries from pregnant mice. Enhanced gap junction communications in the uterine bed of pregnant animals were also demonstrated. Therefore, pregnancy adaptations in the mouse include a reduction of myogenic tone in small mesenteric and main uterine arteries.
In agreement with our findings pertaining to small mesenteric arteries, myogenic reactivity has been shown to be reduced in small mesenteric and renal arteries in pregnant rats compared with virgin controls (14, 30). In contrast, others (8, 24) have revealed no change in myogenic tone in mesenteric vessels obtained from pregnant rats. Interestingly, it was demonstrated that the presence of intraluminal flow was necessary to reduce myogenic tone in mesenteric arteries from late pregnant rats (31), suggesting that pregnancy alters the interaction between intraluminal forces (pressure and flow) with the arterial wall, thereby causing an overall reduction of vascular tone in pregnancy (31). Our study showed reduced myogenic tone in the absence of flow in mesenteric arteries from pregnant mice, suggesting possible distinct adaptations that may occur in different species in pregnancy.
Our study demonstrated a reduction of myogenic tone in uterine arteries of pregnant mice. In contrast, other studies have reported an enhanced myogenic reactivity in myoendometrial radial uterine arteries from late pregnant rabbits (6) and uterine radial arteries from late pregnant rats (32). This disparity could be explained by the anatomical location of the uterine vessels and also species variation. Because of the small size of the mouse, we have used the main uterine artery in contrast to the branched uterine arteries used in the above studies.
The endothelium can be a modulator of myogenic tone (29). In our study, removal of endothelium enhanced myogenic tone only in the pregnant mice. These findings are in agreement with studies that showed endothelium removal enhanced myogenic responses in small renal arteries (14) and small mesenteric arteries from pregnant rats (33). The endothelial modulation of myogenic tone in pregnancy is likely mediated by vasodilators such as NO.
The role of endothelium-derived NO in peripheral vasodilation during pregnancy is far from established. Pressure-induced myogenic tone was shown to be modulated by endothelium-derived NO in studies involving pregnant rats (14, 33). These findings are further supported by a study of myometrial resistance arteries obtained from normal pregnant women at term (23). Myogenic tone appeared to be modulated by endothelium-derived NO in the uterine circulation during normal pregnancy (23). In contrast, some studies showed that NO did not modulate myogenic tone, but did alter flow-mediated vasodilation, in subcutaneous resistance vessels from normal pregnant women (7). Similar findings suggest that NO regulates flow-mediated vasodilatation in mesenteric arteries taken from pregnant rats during late gestation, as well as from human fetal placental vasculature (8, 25).
In the present study, we demonstrated that endothelium-derived NO is also involved in modulation of myogenic tone in mouse pregnancy. There was significant enhancement of myogenic tone in the presence of NOS inhibitor in pregnant mesenteric and uterine arteries >60 mmHg. Enhanced myogenic tone after endothelial removal was comparable to NOS inhibition. Inhibition of PGHS pathway in the mouse vasculature did not contribute to the enhancement of myogenic tone in either nonpregnant or pregnant mice. Our finding is in agreement with a study on resistance myometrial arteries that showed absence of PGHS pathways on myogenic tone (22). These results overall indicate that endothelial-derived NO modulates myogenic tone in mesenteric and uterine arteries isolated from pregnant mice.
Hyperpolarizing factors may be an important component in the increased
endothelium-dependent vasodilation observed during pregnancy (2,
15, 19, 34, 37). In addition, hyperpolarization of vascular
smooth cells may also be a contributing factor to reduced myogenicity
in rat pregnancy (30). Recent studies suggest that
hyperpolarizing factor(s) may pass from endothelial cell to smooth
muscle cell via myoendothelial gap junctions leading to reduced
vascular tone (18, 35). Connexons are formed by the
association of six connexin proteins, which constitutes a gap junction.
Connexin 43, in addition to connexin 40 and connexin 37, are
predominantly located in the vascular system where they may play a role
in vasomotor function (4, 26). Connexin 43 mRNA levels
were shown to be elevated in the uterus and uterine and mesenteric and
thoracic arteries in pregnant rats (10). A recent study
(20) showed that gap junctions are involved in the
transfer of vasodilatory (hyperpolarizing) factors in human myometrial
vessels in normal pregnancy. In the present study, we evaluated the
potential role of gap junctional communications in mediating
endothelium-dependent vasodilation in pregnancy. With the use of a
selective blocker of gap junctions 18- GA, we have demonstrated
enhanced myogenic tone only in the uterine vessels from pregnant mice,
without any effect on mesenteric arteries from pregnant mice and
arteries from nonpregnant mice. Thus it may be possible that gap
junctions (especially in the uterine vascular bed) may provide a
pathway through which NO and other hyperpolarizing factors may exert
their effects.
In conclusion, our study demonstrated reduced myogenic tone in small mesenteric and main uterine arteries from late pregnant mice. This phenomenon may be a result of increased endothelium-derived NO as well as enhanced gap junctional communications, allowing for the adaptive increase in vasodilatation during pregnancy. The importance of this study relates to the provision of novel information about the mechanisms involved in reduced myogenic tone during normal mouse pregnancy and thus provides a foundation for understanding vascular adaptations to pregnancy in both normal and genetic knockout mice models.
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ACKNOWLEDGEMENTS |
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This project is supported by Canadian Institute of Health Research (CIHR). S. T. Davidge obtains salary support from CIHR and the Alberta Heritage Foundation for Medical Research (AHFMR). S. Veerareddy is funded by the Department of Ob/Gyn through a Wyeth-Ayerst Fellowship Award and University of Alberta Perinatal Research Centre. C. M. Cooke is supported by a graduate studentship from CIHR and AHFMR. P. N. Baker is supported by Tommys: The Baby Charity.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. T. Davidge, Perinatal Research Centre, 232 HMRC, Depts. Ob/Gyn and Physiology, Univ. of Alberta, Edmonton, Alberta T6G 2S2, Canada (E-mail: sandra.davidge{at}ualberta.ca).
This article belongs to a collection of papers accepted in response to the Editor's special call for papers entitled "Mechanisms of vascular myogenic tone."
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.
August 22, 2002;10.1152/ajpheart.00593.2002
Received 12 July 2002; accepted in final form 19 August 2002.
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METHODS
RESULTS
DISCUSSION
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) compared with nonpregnant mice (NP, n = 16, 
, P < 0.001).
-nitro-L-arginine methyl ester
(L-NAME) [nitric oxide synthase (NOS) inhibitor] and
meclofenamate (PGHS inhibitor) on myogenic tone in mesenteric arteries
from nonpregnant and pregnant mice. A: myogenic tone was
unaltered by both inhibitors in mesenteric arteries from nonpregnant
mice; B: myogenic tone was enhanced in presence of
L-NAME and meclofenamate in mesenteric arteries from
pregnant mice. P < 0.001 for L-NAME vs.
control (shown in B) and P < 0.002 for
L-NAME and meclofenamate vs. control.
