|
|
||||||||
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| |
ABSTRACT |
|---|
|
|
|---|
Pregnancy is associated with increases in cardiac output and uterine blood flow (UBF) and a fall in systemic vascular resistance. In ovine pregnancy, UBF rises from ~3% of cardiac output to ~25% at term gestation, reflecting a >30-fold rise in UBF by term. This increase in UBF supports exponential fetal growth during the last trimester and maintains fetal well-being by providing excess oxygen and nutrient delivery. These hemodynamic changes are associated with numerous hormonal changes, including increases in placental steroid hormones and enhanced activation of the renin-angiotensin and sympathetic nervous systems, all of which are believed to modulate systemic and uterine vascular adaptation and vascular reactivity. Systemic pressor responses to infused ANG II are attenuated in normotensive pregnancies and the uteroplacental vasculature is even less sensitive, suggesting development of mechanisms to maintain basal UBF and permit the rise in UBF necessary for fetal growth and well-being. The effects of ANG II on the uteroplacental vasculature are reviewed, and the mechanisms that may account for attenuated vascular sensitivity are examined, including ANG II metabolism, vascular production of antagonists, ANG II-receptor subtype expression, and the role of indirect mechanisms.
uterine blood flow; sheep; receptors; angiotensin II metabolism; pregnancy
| |
INTRODUCTION |
|---|
|
|
|---|
PREGNANCY IS A UNIQUE physiological state that is responsible for successful propagation of mammalian species. Normal mammalian pregnancy is associated with numerous hemodynamic changes, e.g., in sheep, cardiac output increases >50%, systemic vascular resistance (SVR) falls, arterial blood pressure decreases modestly, and cardiac output is redistributed (36, 91, 114, 116). Unique to pregnancy is a rise in uterine blood flow (UBF), which in sheep is >30-fold and reflects an increase from 3-5% of cardiac output in the nonpregnant state to 20-25% at term gestation (36, 108, 113, 114, 116, 124). This exponential rise in UBF predominantly occurs in the last two-thirds of gestation. It is associated with placentation, i.e., angiogenesis, followed by vasodilation and is essential for normal fetal growth and well-being, providing the oxygen and nutrient delivery required for the exponential fetal growth that parallels the rise in UBF in the last trimester (113, 116). As UBF increases in pregnancy it is redistributed within the uterus, and at term >85% of total UBF is directed toward the maternal placental vascular bed (87, 115). Thus the rise in UBF is predominantly due to exponential increases in placental blood flow (108, 124). These cardiovascular changes are associated with modifications in the endocrine milieu, representing placental- and nonplacental-derived substances, including steroid hormones and products of the renin-angiotensin system (RAS). Although there is an apparent interdigitation between the hemodynamic and endocrine alterations occurring in pregnancy, the precise relationships remain unclear.
In addition to the general cardiovascular modifications described,
there are changes in vascular responsiveness or sensitivity to several
vasoconstrictors. For example, pregnant women develop attenuated
pressor responses to infused ANG II and
-adrenergic agents (1,
20, 49). These changes occur early in pregnancy and are of
interest because the refractoriness to ANG II is lost as early as the
midtrimester in women who later develop pregnancy-induced hypertension
(49, 141). It has been proposed that by understanding this
particular aspect of pregnancy one may subsequently determine the
pathogenesis of this hypertensive disorder, which affects 5-10%
of pregnant women (36). The uterine vascular bed also is
refractory to ANG II in normotensive pregnancies (44, 95, 125), and, similar to the systemic vasculature, this is lost in
the presence of hypertension (45), which is often
paralleled by a fall in UBF, as well as uterine oxygen and nutrient
delivery, and compromised fetal growth and well-being. Thus it would be important to determine what adaptive mechanisms modulate the systemic and uterine vascular beds during normal pregnancy and if these mechanisms are similarly affected in the presence of hypertensive disease.
The changes in the hormonal milieu in normotensive pregnancies are
extensive, and, although they have been reasonably well characterized,
their purposes are far from understood. It is believed that ovarian-
and placental-derived estrogens and progesterone participate in
modifying vascular reactivity and may facilitate the widespread
vasodilation observed in pregnancy (116). The increase in
the activity of the RAS in pregnancy has received a great deal of
attention. It is associated with increases in the synthesis of renin,
angiotensinogen of hepatic and nonhepatic origins, and ANG II,
resulting in increases in plasma renin activity and circulating levels
of ANG II (77, 132, 138). The purpose for these changes
also remains unclear, but may be related to the mechanisms responsible
for modulating the extensive vasorelaxation associated with
normotensive pregnancy. That is, they may participate in maintaining
vascular tone (109) and the rise in cardiac output. Evidence for this is indirectly obtained from studies in which nonspecific blockade of the ANG II receptor (ATR) and/or the
-adrenergic receptor after estrogen exposure in nonpregnant sheep
resulted in substantial falls in mean arterial pressure (MAP; 38).
However, this remains to be proven in pregnancy. It also is unclear why the placental unit has the capacity to synthesize many components of
the RAS (14, 58, 137). Maybe they participate in local modulation of uterine vascular tone or angiogenesis early in gestation. Although this too remains unanswered, it may be essential to our understanding of the systemic and uterine hemodynamic changes in pregnancy.
In the present review, I will examine several aspects of the relationship between ANG II, the primary vasoactive agent produced by the RAS, and the uteroplacental circulation. Because much of our knowledge regarding these interactions has been derived from extensive animal studies, in large part from the chronically instrumented ovine species, I will use these data to describe our present state of knowledge, but I will refer to the human when reasonable correlates are available, thereby demonstrating the similarities that exist between the species.
| |
ANG II AND VASCULAR REACTIVITY: SYSTEMIC VS. UTERINE |
|---|
|
|
|---|
Normal pregnancy is associated with attenuated pressor responses
to systemic infusions of ANG II (1, 20, 49, 141). This is
detected as early as the midtrimester and is no longer evident after
parturition (1). Several species develop a similar refractoriness during pregnancy (9, 11, 104, 120). In
studies from our laboratories we (120) not only
observed attenuated pressor responses to continuous systemic infusions
of ANG II that were evident early in ovine gestation, but also that the
dose-response curves generated from steady-state responses in
nonpregnant and pregnant ewes were strikingly similar to those
published for nonpregnant and pregnant women (141).
Furthermore, the pressor dose, i.e., the dose required to elicit a
20-mmHg rise in MAP, in nonpregnant and pregnant ewes was the same as
that reported for women (141). We (81) later
observed that pregnant ewes, similar to pregnant women
(20), also develop refractoriness to the pressor effects of systemic infusions of
-agonists. These observations, therefore, support the value of using chronically instrumented ewes as a model in
which to investigate the mechanisms responsible for the adaptive
changes in the cardiovascular system associated with normal pregnancy
and may permit us to subsequently develop better strategies to
investigate and understand hypertensive diseases in pregnant women.
In our initial studies of the systemic responses to ANG II in
pregnancy, we implanted electromagnetic flow probes on both main
uterine arteries to continuously monitor UBF, having previously demonstrated the reliability of this method (124). We
observed a dose-dependent response in UBF, but little or no change
occurred until the systemic dose of ANG II exceeded 0.08 µg · kg
1 · min
1 (Fig.
1), which results in pharmacologic plasma
levels of ANG II (93). Furthermore, there was a biphasic
response in UBF during systemic ANG II infusions (Fig.
2). That is, during ANG II infusions >0.1 µg · min
1 · kg
1
there was a rise in UBF that occurred after the more rapid increase in
MAP, followed by a progressive fall in UBF although MAP remained stable, achieving a steady state by 3-6 min. In earlier studies using systemic bolus doses of ANG II and/or anesthetized animals, ANG
II was considered a uteroplacental vasodilator, because UBF rose soon
after ANG II infusions started (5, 48, 69, 89, 134, 142).
These studies, however, 1) frequently used bolus doses of
the peptide, 2) were often limited to examining the initial phase of the UBF response, 3) did not always consider the
simultaneous changes in perfusion pressure, and 4) were
frequently performed in acute animal preparations, which modifies
vascular responses to several agents (116, 123). When we
(95) examined the change in uterine vascular resistance
(UVR) in chronically instrumented animals across a broad range of
continuous systemic ANG II doses and only used the steady-state
responses, there were only increases in UVR at all doses studied,
demonstrating that ANG II was always a uterine vasoconstrictor in
pregnant sheep over a broad range of doses (Fig.
3). This was consistent with observations
by Cohen et al. (28) in anesthetized rabbits and is now
generally accepted (26, 151). On further inspection of the
uterine responses to systemic ANG II infusions, we also observed that
the rise in UVR was significantly less than the rise in SVR at all
doses of ANG II <2.3 µg/min (Fig. 3), suggesting that at
physiological and even pharmacologic doses (93) the
uterine vascular bed was even "less sensitive" to the
vasoconstricting effects of ANG II than the systemic vasculature as a
whole.
|
|
|
To understand the mechanisms responsible for the biphasic UBF response
to ANG II, we (95) examined the simultaneous relative changes (percent change, %
) in perfusion pressure or MAP, UVR and
UBF. Because each hemodynamic parameter has a different unit of
measurement, the raw data cannot be easily compared; but by controlling
for baseline values and calculating the percent change, a comparison of
the relative responses is obtained, and any interaction between the
three variables is easily assessed (95). When this simple
rearrangement was performed and the data analyzed using dose and
duration of ANG II infusion in the steady state, it became apparent why
others had concluded that ANG II was a uterine vasodilator. At doses of
ANG II
1.15 µg/min, which generally results in physiological plasma
concentrations (93), there was a rise in MAP that always exceeded the rise in UVR and was associated with an increase or no
change in UBF (Fig. 4). However, when the
dose of ANG II exceeded 2.3 µg/min, resulting in high pharmacological
plasma levels (93), the relative rise in UVR exceeded the
increase in MAP and UBF fell. Thus changes in UBF are highly dependent
on the difference in the relative responses in MAP or perfusion
pressure and local UVR (55, 70, 148). A similar
relationship has been observed in studies of UBF and ANG II in pregnant
dogs and guinea pigs and confirmed in the ewe (26, 37,
151). When the responses to individual ANG II doses are analyzed
across time, a strikingly similar relationship is seen. That is, at
"all" doses of ANG II studied, the change in MAP occurs more
"rapidly" than the rise in UVR; thus UBF always increases in the
initial response to systemic ANG II infusions (Fig.
5). However, if the dose of ANG II
ultimately increases UVR greater than MAP in the steady-state response,
e.g., 11.5 µg/min (Fig. 5), UBF clearly falls at this time. Until
recently, we and others did not appreciate the meaning of this
difference in the timing of the systemic and uterine responses to
systemic ANG II infusions. This will be addressed later. Nonetheless,
the conclusions from these studies are 1) ANG II is only a
uterine vasoconstrictor in all species studied under unstressed
conditions as reported for other vascular beds, 2) the
uterine vasculature is less sensitive to systemic ANG II infusions than
the systemic vasculature at physiological plasma levels of the peptide,
and 3) UBF responses in pregnancy must be assessed with
consideration to simultaneous alterations in perfusion pressure. In
other words, UBF is "protected" from the vasoconstrictor effects of
elevated circulating ANG II that occurs during pregnancy (77,
132, 138). With the advent of pulse-gated Doppler for measuring
UBF or resistance in women, Erkkola et al. (44) observed
similar differences in uterine and systemic sensitivity to infused ANG
II in normotensive pregnant women. They later reported that this
uterine refractoriness, as with systemic refractoriness, was lost in
women who developed hypertensive disorders (45). These
data, therefore, provide additional evidence that the ewe is an
excellent model in which to study normal cardiovascular adaptation in
pregnancy and, in particular, the changes in uteroplacental adaptation.
Furthermore, although the placental morphology differs between women
and sheep (116), changes in uterine vascular reactivity
appear to be similar.
|
|
Thus far, the data provide insight into changes in total UBF and UVR.
The pregnant uterus, however, is comprised of at least three tissues:
the myometrium, which makes up the bulk of uterine weight, the
endometrium, and the placental cotyledons, the site of gas and nutrient
exchange. In nonpregnant ewes these tissues (caruncles in the
nonpregnant state are the subsequent sites of implantation and
represent the cotyledons) receive a similar proportion of UBF, ~33%
(123, 124). However, UBF is gradually redistributed during
pregnancy, and the placental portion of UBF increases
disproportionately, accounting for
85% of total UBF by term
(87, 108, 115). Because this portion of UBF is responsible
for fetal growth and well-being, it is important to know if ANG II
alters placental blood flow. To accomplish this, studies were performed
in conscious pregnant ewes using radionuclide-labeled microspheres,
which permit the simultaneous measurements of cardiac output and its
distribution, SVR, the responses of the three uterine tissues, and
responses by nonuterine tissues at specific time points (114,
124, 125). Flow probes were also implanted on each uterine
artery to continuously monitor UBF and more accurately time the
microsphere infusions. As anticipated from earlier studies, the
relative rise in UVR during systemic ANG II infusions <1 µg/min was
less than the rise in SVR, confirming the uterine refractoriness
previously noted with flow probe measurements (95). At ANG
II doses >5 µg/min, the %
UVR exceeded %
SVR and MAP, thus UBF
fell. Importantly, the lower ANG II dose results in estimated plasma
levels of the peptide of ~200 pg/ml (93), which resemble
that observed in normotensive pregnant women (77). The
higher doses, however, result in plasma levels of ANG II >2,000 pg/ml,
which are nonphysiological. Placental blood flow and vascular
resistance were unchanged with 0.573 and 5.73 µg ANG II/min (Fig.
6), and blood flow fell only 16% with
the highest dose studied, 11.5 µg/min. In contrast, endometrial and
myometrial blood flows significantly decreased and vascular resistance
rose with all three doses (Fig. 6). Thus the placental circulation is
refractory to a wide range of systemic ANG II doses. When the
distribution of UBF was calculated, the proportion going to the
placental cotyledons actually rose from 74% before ANG II infusion to
90% with the pharmacologic dose of the peptide, further demonstrating
the protection afforded maternal placental blood flow through increases
in perfusion pressure and decreases in blood flow to the other uterine
tissues.
|
It had been suggested that the differences in the responses in total
SVR and UVR during systemic ANG II infusions might be due to a greater
sensitivity of the nonreproductive compared with reproductive tissues
(95). However, data to support this were lacking. This was
addressed in the microsphere studies when nearly all of the
nonreproductive tissues, including the kidney, adrenal, and adipose,
were observed to consistently decrease blood flow and increase vascular
resistance at all three doses of ANG II studied (Fig.
7). This provided conclusive evidence of
the differences in vascular sensitivity to ANG II that exist between
various tissues/organs in normal gestation. Of interest, myometrial and
endometrial sensitivities resembled that in peripheral or
nonreproductive tissues. Curran-Everett et al. (37)
reported similar differences between uteroplacental and
nonuteroplacental responses to ANG II in late-gestation guinea pigs.
These differences in vascular reactivity are intriguing, because they
suggest that ANG II may be a safer pressor agent for treating
hypotensive episodes in gravid women than the standard use of
-agonists. Support for this is obtained from observations in women
and sheep that ANG II has greater effects on SVR and MAP than UVR,
thereby having minimal effects on UBF. Moreover, all
-agonists
studied have greater effects on UVR than SVR (53, 56, 81, 99,
110, 117, 126), which may be accentuated in pregnant women with
hypertensive disease, but has not been studied.
|
Although existing data supported the thesis that the uterine
vasculature in pregnancy was less responsive to systemic ANG II
infusions than the systemic vasculature, it was unclear if this was an
inherent characteristic of the uterine vascular bed or due to some
adaptive change(s) that occurs in pregnancy. Cox et al.
(34) addressed this by comparing systemic and uterine responses to systemic ANG II infusions in pregnant and nonpregnant ewes
with flow probes on both main uterine arteries. MAP rose dose
dependently in both groups, but as expected, the %
MAP in nonpregnant ewes greatly exceeded that in pregnant animals at "all"
doses, values increasing 40-65% in the former vs. 20-50% in
pregnant ewes, P < 0.0001. Although UVR rose dose
dependently in both groups, the responses in nonpregnant ewes were
substantially greater at all doses studied (Fig.
8), values rising 80-350% vs. 25-90% in pregnant ewes (P < 0.0001). Thus UBF
fell only 20% in pregnant ewes with the highest ANG II dose studied
compared with 60% in nonpregnant ewes (Fig.
9). When the simultaneous relative changes in systemic and uterine responses were compared, pregnant ewes
had greater relative increases in MAP than UVR at physiological doses,
confirming prior observations (95, 125). In contrast, nonpregnant animals had greater increases in UVR than MAP at all ANG II
doses, resembling responses to
-agonists (81); e.g., with an estimated plasma ANG II level of 0.8 ng/ml the %
UVR was ~130% vs. ~50% for MAP. These data (34), therefore,
demonstrate that the uterine vasculature "develops" the
pregnancy-associated attenuation in ANG II-induced vasoconstriction,
which also occurs with
-agonists (81). Furthermore,
they also suggest that the differences in systemic and uterine
responses to systemic ANG II infusions in normal pregnancy are not
inherent to the uterine vasculature but are due to pregnancy-related
changes. This could reflect the growth and development of the less
responsive placental vasculature, which accounts for >85% of UBF
(125). Alternatively, it might be due to modifications in
ANG II metabolism, synthesis of local ANG II antagonists, changes in
uterine vascular smooth muscle, alterations in ANG II receptor (ATR)
expression and/or binding, or any combination of factors.
|
|
| |
ANG II AND VASCULAR REACTIVITY: METABOLISM OF ANG II |
|---|
|
|
|---|
One potential explanation for the attenuated systemic pressor
responses to infused ANG II in pregnancy is that the peptide is cleared
from the circulation at a greater rate than that observed in the
nonpregnant state. This also would explain the attenuated uterine
vascular sensitivity associated with pregnancy, but not the difference
between systemic and uterine sensitivity. It had been suggested that
ANG II metabolism was greater in pregnancy and due to increases in
circulating levels of placentally derived aminopeptidases (103,
140) or through enhanced maternal placental clearance
(92), reflecting placental aminopeptidases that also prevent transplacental transport of ANG II to and from the fetal compartment (6, 51, 64, 75, 107). To address this, Naden et al. (93) measured the metabolic clearance of ANG II
(MCRANG II) in nonpregnant and near-term pregnant ewes.
There was the anticipated difference in pressor responses to systemic
ANG II infusions, but over a range of ANG II doses there was no
difference in the MCRANG II, 56.2 ± 6.3 and
55.9 ± 4.3 ml · min
1 · kg
1,
respectively. They also reported that plasma levels of ANG II achieved
during steady-state infusions were proportional to the infusion rate in
both groups and proposed this would permit investigators to calculate
the estimated arterial ANG II concentrations during studies of the
effects of systemic steady-state infusions. The values for
MCRANG II in nonpregnant ewes are consistent with earlier
observations in nonpregnant sheep (46, 47) and the human
(40, 65, 100). Magness et al. (77)
subsequently reported that the MCRANG II was not
significantly different in normotensive nonpregnant and pregnant women,
85 ± 10 vs. 68 ± 3 ml · min
1 · kg
1,
respectively. Moreover, these values resemble those observed in the
ewe, demonstrating another similarity between species (93, 121). The half-life for ANG II was ~49 s, which also is
consistent with other species and women (40, 42). When the
removal rate of ANG II by circulating aminopeptidases was
examined, the estimated half-life was ~10 min (47),
which is inconsistent with removal rates seen in vivo. Thus increases
in circulating aminopeptidase enzymes associated with pregnancy
probably play a minor role in ANG II removal. It also was determined
that the increased volume of distribution in pregnancy could not
account for the attenuated responses.
Subsequently, Rosenfeld et al. (121) examined ANG II
clearance across the uteroplacental vascular bed of pregnant sheep. They confirmed the observations of Naden et al. (93) for
maternal MCRANG II in pregnant sheep and reported that
uteroplacental clearance averaged 20 ± 6% in term animals. This
is in sharp contrast to a fetal MCRANG II of 680 ml · min
1 · kg
1 and >90%
clearance of ANG II across the fetal placental vascular bed (121,
135). If the adult rat kidney clears ANG II at 1 µg · min
1 · g kidney
1
(73) and ovine kidneys weigh ~180 g, renal clearance
could account for removal of a predominant portion of ANG II from the maternal circulation, which is consistent with the data for
uteroplacental clearance. Therefore, in women and sheep neither the
attenuated systemic nor uterine responses to infused ANG II in
pregnancy reflect enhanced ANG II removal from the circulation. More
recently, Iyer et al. (62) reported that neither ATR
subtype is directly involved in ANG II clearance in hypertensive adult
male rats. However, the type 2 ATR (AT2R) appeared to
enhance ANG II clearance. Although the role of the ATR subtypes in
MCRANG II has not been examined in pregnancy, the
AT2R subtype predominates in the uterine vascular bed of
women and sheep (see below; 32, 35), and its role in uteroplacental ANG
II clearance has not been examined.
| |
ANG II AND VASCULAR REACTIVITY: LOCAL ANTAGONISTS |
|---|
|
|
|---|
Pregnancy is associated with enhanced vascular production of several vasoactive substances, including PGs (52, 78, 82), estrogens (36, 116), and nitric oxide (NO; 133), which may increase organ and tissue blood flows and antagonize local vascular responses to ANG II or other vasoconstrictors so that blood flow is maintained. The existing literature on PGs in pregnancy is immense and cannot be completely examined in this review; therefore, only pertinent points relative to ANG II and UBF will be addressed.
During pregnancy there are increases in circulating PGs, particularly vasodilating PGs (52, 82), and in the uterine synthesis of these compounds (78, 142, 149). Furthermore, treatment with cyclooxygenase inhibitors has been shown to increase pressor responses to infused ANG II in some, but not all, species during pregnancy (29, 59, 151, 152). Similarly, infusion of PGs into intact animals has had variable effects on UBF. For example, systemic infusions of prostacyclin (PGI2) in pregnant ewes and guinea pigs are associated with a fall in MAP and UBF (26, 111, 151), whereas local intra-arterial infusions have no effect on MAP but consistently increase UBF (24, 72). In nonpregnant ewes, PGE2 is a uterine vasodilator, but in pregnancy it decreases UBF (25, 72). We now appreciate that many of these contradictory and confusing observations reflect the mode of administration and the simultaneous effects on MAP or perfusion pressure and UVR, whereas in other instances this has been due to increases in myometrial contractility occurring simultaneously with the vascular responses, which obscures vasodilation by increasing intramural pressure (24, 25, 98, 112).
To address these confounding variables, Magness et al.
(79) studied in vitro PGI2 synthesis in intact
uterine and systemic arteries, the latter represented by omental
arteries, at different times in reproduction. Basal PGI2
synthesis by uterine and systemic arteries from near-term pregnant ewes
was 10- and 3-fold greater, respectively, than synthesis by vessels
from nonpregnant animals, and values fell in the postpartum period,
returning to nonpregnant rates by 2 wk postpartum (Fig.
10). Moreover, in pregnancy and the
early postpartum period (~1 wk), basal PGI2 synthesis in
uterine arteries exceeded that by systemic arteries. This difference
was not evident in systemic and uterine arteries collected from
nonpregnant and late postpartum ewes, demonstrating a reversible
pregnancy-induced rise in basal vascular PGI2 synthesis,
which could be involved in the vasodilation and attenuated
vasoconstrictor responses seen in both vascular beds. These
investigators also observed for the first time that incubation of
uterine arteries from pregnant and early postpartum ewes with ANG II
resulted in a further dose-dependent increase in PGI2
synthesis, as reported in the renal and splenic vascular beds
(41, 88). However, the maximum values achieved with
10
5 M ANG II were greatest in arteries from near-term
pregnant ewes, 762 ± 145 vs. 229 ± 47 pg · mg
1 · h
1
(P < 0.001), respectively. This was not seen in
systemic vessels from any group of animals and was inhibited by the
nonspecific ATR antagonist saralasin. Thus a receptor-mediated
mechanism exists in pregnant ovine uterine arteries that has the
potential to further attenuate the vasoconstricting effects of infused
and endogenous ANG II (or other vasoconstrictors) and account for the
differential uterine and systemic responses described
(95). This ANG II-induced rise in uterine artery
PGI2 is derived solely from the endothelium (83,
85), which accounts for ~60% of basal PGI2
synthesis in pregnant uterine and systemic arteries, is mediated by
activating type 1 ATR (AT1R; 32, 86), which are upregulated
in pregnancy (10), and is calcium dependent
(83). Recently, Janowiak et al. (63) reported
that uterine artery endothelium cyclooxygenase-1 is also upregulated in
ovine pregnancy, whereas changes in uterine artery smooth muscle
expression are less clear. Yoshimura et al. (156) confirmed the
stimulatory effects of ANG II on in vitro PGI2 synthesis by
uterine arteries from pregnant ewes, but reported that this effect was
not evident in the maternal placental vasculature, which had
PGI2 and PGE2 synthesis rates that were only
25-30% of that seen in the uterine artery. Glance et al.
(50) observed a similar lack of effect of ANG II on PG
synthesis in the human placenta. The markedly attenuated placental
responses to ANG II, therefore, may not be due to local basal or
stimulated PG synthesis. In preliminary studies, ANG II also increased
human uterine artery PGI2 synthesis (unpublished
observations), but this requires additional study.
|
If basal uterine artery PGI2 synthesis increases in normal
pregnancy as well as uterine synthesis of other PGs, it is logical to
assume that PGs may modulate basal UBF and uterine vascular sensitivity
to vasoconstrictors. However, indomethacin, a nonspecific cyclooxygenase inhibitor, only transiently alters basal UBF, UVR, and
SVR, with values returning to baseline within 15-20 min despite falling PG levels, whereas meclofenamate has no effect (89, 94,
151). Therefore, several investigators have concluded that the
rise in basal uterine PG synthesis in pregnancy does not regulate basal
UVR and UBF. Alternatively, ANG II-induced increases in uterine artery
PGI2 synthesis plus the increase in basal synthesis associated with pregnancy (79) may protect the
uteroplacental vascular bed from the effects of ANG II or other
vasoconstrictors. This was addressed in intact pregnant ewes by
infusing systemic ANG II in the absence or presence of "local"
intra-arterial infusions of indomethacin, a paradigm that would remove
any confounding systemic effects (84). In the absence of
indomethacin, systemic ANG II infusions increased uterine venous
PGI2 from 192 to 1,044 pg/ml dose dependently
(P < 0.05) with a modest effect on arterial levels due
to the large increase in uterine synthesis (84). Thus in
vitro observations (79) were replicated in intact
conscious animals. Although local indomethacin did not alter basal UBF, UVR, or MAP, uterine venous and venoarterial concentration differences of PGI2 fell ~75%, the latter decreasing from 123 ± 29 to 28 ± 14 pg/ml. Furthermore, ANG II no longer affected
uterine venous PGI2, with values remaining ~50 pg/ml.
However, the ANG II-mediated UVR dose-response curve in the treated
uterine horn was shifted upward and to the left, and UBF now fell at
all systemic doses of ANG II (Fig.
11A). The contralateral
uterine horn was unaffected (Fig. 11B) as was the response
in MAP. Thus uterine vascular responses to systemic ANG II infusions
after local cyclooxygenase inhibition resembled those seen in
nontreated nonpregnant ewes (34). Although this is
consistent with observations by McLaughlin et al. (89), it
differs from that observed by Woods (152) in pregnant dogs. In
those studies, uteroplacental sensitivity to ANG II was unaffected by
PG inhibition with meclofenamate. This might be due to differences in
species or the cyclooxygenase inhibitor used.
|
From these observations it is possible to conclude that total PG
synthesis increases during pregnancy in several species, and uterine
synthesis increases dramatically. However, existing data do not
consistently support the hypothesis that increases in basal PG
synthesis account for the systemic or uterine vasodilation characteristic of pregnancy. There is evidence that PGs may modulate uterine and systemic responses to vasoconstrictors, in particular, responses to systemic infusions of ANG II and
-agonists (8, 27). Importantly, these studies and those noted earlier again demonstrate the importance of examining responses to local and systemic
infusions of inhibitors, PGs, and maybe ANG II, which will be addressed later.
More recently, there has been accumulating evidence that vascular NO
synthase (NOS) activity increases in pregnancy and may play a pivotal
role in the vasodilation and attenuated vascular reactivity associated
with pregnancy (see review, Ref. 133). For example,
systemic and peripheral inhibition of NOS increases responsiveness to
infused ANG II in pregnant but not nonpregnant rats (2, 74,
97), suggesting NOS is upregulated in the peripheral vasculature
in pregnancy and serves in part to attenuate responses to ANG II and
other vasoconstrictors. Uterine artery endothelial NOS also is
elevated in pregnancy and is associated with substantial increases in
uterine cGMP production (86, 119, 133, 153). However, its
role in modulating the >30-fold rise in UBF at term pregnancy is
unclear, because short-term intra-arterial infusions of
N
-nitro-L-arginine methyl
ester, a nonspecific NOS inhibitor, decreased uterine cGMP
synthesis without altering basal UBF (133).
Several investigators recently reported that ANG II stimulates local NO synthesis, and pretreatment with an NOS antagonist enhances constrictor responses to infused ANG II (39, 139). Furthermore, this may be mediated through activation of vascular smooth muscle AT2R (130, 144). As discussed later, this may be important in the uterine circulation. In ovine pregnancy, ~80% of uterine artery NOS activity is located in the endothelium (85, 86); in contrast to prostacyclin, this does not differ from that observed in the omental artery. As an indirect measure of NOS activity, uterine artery cGMP synthesis increases approximately twofold in the presence of 50 nM ANG II. Unlike PGI2, this is not unique to the uterine artery of pregnant animals and is observed in systemic arteries from both groups. Nonetheless, total cGMP production by uterine arteries, i.e., basal plus ANG II-stimulated, is 2.5-fold greater than that by omental arteries, ~1,000 vs. 400 fmol/mg of tissue weight, respectively, which could contribute to the attenuated uterine responses to infused ANG II in pregnancy and the differences between the uterine and systemic responses. In fact, the additive effects of enhanced PGI2 and NO synthesis in the presence and absence of ANG II may be important. This, however, has not been well studied to date and requires verification and testing. It also is unclear if ANG II directly or indirectly increases uterine artery endothelial NOS activity (130). It is intriguing, however, that estrogen upregulates both endothelial NOS in endothelium and neuronal NOS in smooth muscle of uterine arteries from nonpregnant ewes within 90 min and after daily exposure (119, 127, 146, 147) and is associated with attenuated systemic pressor responses to infused ANG II (80, 104, 122). Furthermore, uterine responses to ANG II after estrogen treatment are strikingly similar to that observed in pregnant animals, i.e., the rise in UVR is less than the rise in MAP (96), which is opposite that seen in untreated nonpregnant animals (34). Thus placental estrogens may be involved in modifying vascular reactivity in pregnancy.
| |
ANG II AND RECEPTOR EXPRESSION |
|---|
|
|
|---|
It is now clear that at least two subtypes of the ATR are expressed in large mammals, AT1R and AT2R, whereas there are three in the rodent, AT1AR, AT1BR, and AT2R (7, 13, 60, 61). They are considered members of the seven transmembrane-spanning receptor superfamily, are derived from separate gene products, and have only 40% homology. Of particular note, the AT2R is located on the X chromosome, whereas the AT1R is on chromosome 3 (60). The AT1R is the predominant subtype in the adult, is inhibited by the specific antagonist losartan, is G protein coupled, activates phosphoinositide metabolism and phospholipase C, mobilizes intracellular calcium, and mediates vascular smooth muscle contraction as well as most other biologic actions of ANG II (7, 13, 60). In contrast, the AT2R predominates in the developing fetus (30, 54, 150), is the major subtype in fetal and early neonatal vascular smooth muscle (31), does not appear to interact with G proteins (12, 31), and, although its function is relatively unclear, it appears to modify AT1R effects and participate in vascular remodeling (13, 30, 43, 60, 130).
Inasmuch as plasma ANG II is elevated in pregnant women and sheep (76, 77, 93), it stands to reason that the vascular ATR would be downregulated in normotensive pregnancy, which would explain the attenuated pressor responses to infused ANG II. However, in contrast to the myometrium (30, 131), we (30, 76, 118) and others (15, 105) observed that total vascular smooth muscle ATR binding density (Bmax) and affinity were similar in pregnant and nonpregnant animals, and this was true in both the systemic and uterine vasculature. Although Burrell and Lumbers (17) also observed no change in ovine aortic ATR Bmax in pregnancy, uterine artery ATR Bmax rose from ~20 to ~40 fmol/mg protein, the opposite of that anticipated. Nonetheless, the absence of ATR downregulation in pregnancy raises questions regarding the mechanisms regulating ATR expression and turnover in pregnancy, which remain unanswered. While this is not the subject of this review, placental steroids may be involved (68, 128). When Cox et al. (32) determined ATR subtype expression in vascular smooth muscle throughout ovine reproduction, the AT1R was the predominate receptor in all vascular beds examined except the uterus, where the AT2R accounted for 75-90% of total binding in uterine artery smooth muscle from nulliparous, pregnant, postpartum, and nonpregnant ewes. Similar observations were made in uterine arteries from nonpregnant and pregnant women (35), again demonstrating the striking similarity between the two species. The only other adult vascular bed with AT2R predominance is the rat cerebral vasculature (145). This lack of change in vascular ATR subtype expression in pregnancy differs from that in the myometrium of women and sheep, where total Bmax not only falls but is associated with AT2R downregulation, resulting in AT1R predominance (30, 35, 131). Burrell and Lumbers (17), however, reported that AT2R Bmax rose from <5 fmol/mg protein to ~38 fmol/mg protein in ovine uterine arteries by term gestation, and although AT2R accounted for ~60% of total binding at term, only 5% was seen in nonpregnant arteries. AT1R binding density was unaltered. Their study differed in that they used uterine arteries that were frozen with intact endothelium and analyzed in the absence of protease inhibitors. It is unclear, however, what accounts for the discrepancy in the two studies. Furthermore, it is unclear why they did not see the rise in AT1R expression reported in uterine artery endothelium in ovine pregnancy (10).
Since AT2R do not mediate smooth muscle contraction
responses (30, 32, 35), yet they account for nearly 85%
of ATR binding in uterine artery smooth muscle, we sought to determine
if this might explain the uterine vascular refractoriness to ANG II in pregnant women and sheep. If so, it would raise important questions regarding the mechanism(s) whereby systemic ANG II infusions increase UVR. Although the majority of studies examining UBF responses to ANG II
used systemic infusions, Clark et al. (26) studied the
effects of both systemic and local intra-arterial ANG II infusions on
UBF and UVR. However, only high doses of the peptide were locally infused, and there were no data given regarding the effects on MAP. We
(34), therefore, performed studies in nonpregnant and pregnant ewes comparing uterine and systemic responses to a wide range
of ANG II doses infused either systemically or locally into the uterine
artery to exclude systemic effects. These doses resulted in arterial
plasma concentrations ranging from physiological, i.e., ~400 pg/ml,
to pharmacologic values, ~2,000 pg/ml. To compare responses,
intra-arterial doses were calculated to attain arterial plasma
concentrations achieved during systemic infusions (93). As
anticipated, systemic ANG II infusions recapitulated previous observations; i.e., uterine and systemic responses were greater in
nonpregnant vs. pregnant ewes, and in pregnant ewes, uterine responses
were less than systemic. In contrast, local intra-arterial ANG II
infusions in nonpregnant and pregnant ewes did not elicit a significant
rise in UVR (Fig. 8) or a fall in UBF (Fig. 9) in the absence of a
systemic pressor response. However, whenever UVR rose and UBF fell
during local ANG II infusions, responses were always delayed and always
followed a rise in MAP (Fig. 12), suggesting that ANG II had to reach the systemic circulation before eliciting a uterine response. Furthermore, the rise in MAP was consistently delayed compared with that seen during systemic ANG II
infusions. This pattern of response resembles that observed in the
initial studies of ANG II, i.e., the fall in UVR always followed the
rise in SVR and MAP (Figs. 2-5). More recently, Lambers et al.
(71) reported vasoconstrictive responses to intra-arterial ANG II infusions in estrogenized nonpregnant ewes. However, the bolus
dose used to show specificity of the response was pharmacologic and is
estimated to result in arterial concentrations >5,000 pg/ml. Furthermore, rises in MAP occurred with all other local doses of ANG II
studied, which are estimated to range from >600 to >6,000 pg/ml.
|
We interpreted our results to mean that the effects of ANG II on the
uterine vascular bed may be mediated by the systemic release of another
more potent vasoconstrictor. This is supported by the predominance of
AT2R binding in uterine vascular smooth muscle and studies
demonstrating that ANG II may enhance catecholamine release (16,
106), delay catecholamine reuptake at the neuromuscular junction
(18), and/or stimulate synthesis and release of smooth muscle endothelin (19). While studies are underway to
examine this, preliminary evidence supports involvement of another
agent (33). Alternatively, simultaneous AT2R
activation may attenuate or inhibit AT1R-mediated increases
in UVR. This is supported by recent studies in nonpregnant estrogenized
ewes and in vitro studies with uterine arteries from pregnant sheep and
rats (71, 90, 157). We also observed ANG II-mediated
constriction of uterine artery rings, which is inhibited by the
AT1R antagonist losartan; however, the responses were quite
small compared with KCl and
-stimulation. We did not see
potentiation by AT2R inhibition or stimulation. Additional
studies are warranted to address this aspect of ANG II-mediated effects.
| |
ANG II AND VASCULAR REACTIVITY: SMOOTH MUSCLE GROWTH |
|---|
|
|
|---|
Although space does not permit a detailed review of this aspect of
the effects of ANG II on the uteroplacental circulation, ANG II is
known to mediate vascular smooth muscle hypertrophy via the
AT1R (21, 102). In in vitro studies of denuded
uterine artery strips from nonpregnant, pregnant, and postpartum sheep, Annibale et al. (3) were unable to elicit reproducible
responses to ANG II, which is consistent with the observation of
AT2R predominance in these vessels (32).
However, responses to KCl and
-agonist stimulation were enhanced in
uterine arteries from pregnant vs. nonpregnant sheep, which was no
longer evident in the postpartum period. In contrast, renal and carotid
artery responses were unaffected by pregnancy. This is consistent with
other studies examining the difference between uterine artery responses
to ANG II and
-agonists (53, 81, 99, 117, 126).
Annibale et al. (4) subsequently reported that the uterine
artery was hypertrophied in pregnancy and contained increased myosin
and actin contents, consistent with observations by Griendling et al.
(57). St. Louis et al. (136) reported similar
increases in responsiveness to agonists by arcuate arteries from
pregnant rats. They concluded that the mechanical properties of these
arteries had changed. Growth and hypertrophy also occur in more distal
uterine arteries from pregnant rabbits and guinea pigs (23, 66,
67, 101). Thus the uterine vascular bed undergoes substantial
growth and remodeling, resulting in uterine artery hypertrophy, but the
mechanism for this is unclear. It could be due to the rise in UBF and
increase in shear stress, increases in circulating ANG II via
AT1R activation, or the increase in local synthesis of
placental estrogens. Obviously, this is an area that deserves further attention.
| |
SUMMARY |
|---|
|
|
|---|
Maintenance and growth of the uteroplacental circulation is essential for the normal growth and well-being of the developing fetus, and prolonged decreases in UBF result in fetal growth restriction, which may also impair fetal tolerance of labor. The RAS is believed to play an important role in modulating cardiovascular adaptation during pregnancy. The development of refractoriness to the vasoconstrictor effects of ANG II is considered an important aspect of this adaptation, because its absence is associated with maternal cardiovascular disease and increases in fetal growth restriction and fetal and neonatal morbidity. In this review I have examined the mechanisms whereby the effects of ANG II on the uterine circulation are normally modulated. Existing data suggest that the predominance of AT2R binding in uterine vascular smooth muscle may be the predominant mechanism responsible for the attenuated uterine responses to infused ANG II in women and sheep. They also suggest that systemic ANG II infusions may mediate their effects on the uterine circulation through the release of other vasoconstricting agents, such as catecholamines. Furthermore, the combined effects of increases in uterine artery basal and stimulated PGI2 and NO synthesis in pregnancy may serve to modify responses to ANG II and these secondary vasoconstrictors. Thus women with pregnancy-induced hypertension and increased uterine sensitivity to infused ANG II may have abnormalities in vascular synthesis of PGs and/or NO, alterations in AT2R function or expression, or marked increases in these secondary vasoconstrictors, such as catecholamines. Evidence for the latter is obtained from studies in women with pregnancy-induced hypertension who appear to have increases in sympathetic outflow (129, 155). Studies are now underway to examine this hypothesis. With the recent advent of genetically engineered models that delete or overexpress various components of the RAS, e.g., angiotensinogen and ATR subtypes, it may be possible to further delineate the importance of each component in normal and abnormal pregnancy adaptation.
| |
ACKNOWLEDGEMENTS |
|---|
My thanks to M. Nero who helped in the preparation of this manuscript, Dr. B. Cox, a valuable collaborator, who provided critical comments on the content and presentation, and to all the people who have contributed to the ongoing studies in my laboratories.
| |
FOOTNOTES |
|---|
This work was supported by National Institutes of Health Grant HD-08783-26 and the George L. MacGregor Professorship in Pediatrics.
Address for reprint requests and other correspondence: C. R. Rosenfeld, Dept. of Pediatrics, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390 (E-mail: charles.rosenfeld{at}utsouthwestern.edu).
| |
REFERENCES |
|---|
|
|
|---|
1.
Abdul-Karim, R,
and
Assali NS.
Pressor response to angiotensin in pregnant and nonpregnant women.
Am J Obstet Gynecol
82:
246-251,
1961[Web of Science][Medline].
2.
Ahokas, RA,
and
Sibai BM.
Endothelium-derived relaxing factor inhibition augments vascular angiotensin II reactivity in the pregnant hind limb.
Am J Obstet Gynecol
167:
1053-1058,
1992[Web of Science][Medline].
3.
Annibale, DJ,
Rosenfeld CR,
and
Kamm KE.
Alterations in vascular smooth muscle contractility during ovine pregnancy.
Am J Physiol Heart Circ Physiol
256:
H1282-H1288,
1989
4.
Annibale, DJ,
Rosenfeld CR,
Stull JT,
and
Kamm KE.
Protein content and myosin light chain phosphorylation in uterine arteries during pregnancy.
Am J Physiol Cell Physiol
259:
C484-C489,
1990
5.
Assali, NS,
and
Westersten A.
Regional flow-pressure relationship in response to angiotensin in the intact dog and sheep.
Circ Res
9:
189-193,
1961
6.
Behrman, RE,
and
Kittinger GW.
Fetal and maternal responses to in utero angiotensin infusions in Macaca mulatte.
Proc Soc Exp Biol Med
129:
305-308,
1968[Medline].
7.
Bernstein, KE,
and
Berk BC.
The biology of angiotensin II receptors.
Am J Kidney Dis
22:
745-754,
1993[Web of Science][Medline].
8.
Berssenbrugge, A,
Anderson D,
Phernetton T,
and
Rankin JHG
The effect of prostaglandin E2 and indomethacin on the placental vascular response to norepinephrine.
Proc Soc Exp Biol Med
159:
281-285,
1978[Medline].
9.
Berssenbrugge, AD,
Goodfriend TL,
Bell DL,
and
Rankin JHG
The effects of pregnancy on the angiotensin II pressor response in the rabbit.
Am J Obstet Gynecol
136:
762-767,
1980[Web of Science][Medline].
10.
Bird, IM,
Zheng J,
Cale JM,
and
Magness RR.
Pregnancy induces an increase in angiotensin II type-1 receptor expression in uterine but not systemic artery endothelium.
Endocrinology
138:
490-498,
1997
11.
Blair-West, JR,
Coghlan JP,
Denton DA,
Scoggins BA,
and
Wintour EM.
The pressor effect of angiotensin II in pregnant sheep.
Aust J Exp Biol Med Sci
50:
739-744,
1972[Web of Science][Medline].
12.
Bottari, SP,
Taylor V,
King IN,
Bogdal Y,
Whitebread S,
and
de Gasparo M.
Angiotensin II AT2 receptors do not interact with guanine nucleotide binding proteins.
Eur J Pharmacol
207:
157-163,
1991[Web of Science][Medline].
13.
Bottari, SP,
de Gasparo M,
Stickelings UM,
and
Levens NP.
Angiotensin II receptor subtypes: characterization, signaling mechanisms, and possible physiological implications.
Front Neuroendocrinol
14:
123-171,
1993[Web of Science][Medline].
14.
Brar, HS,
Do YS,
Tam HB,
Valenzuela GJ,
Murray RD,
Longo LD,
Yonekura ML,
and
Hsueh WA.
Uteroplacental unit as a source of elevated circulating prorenin levels in pregnancy.
Am J Obstet Gynecol
155:
1223-1226,
1986[Web of Science][Medline].
15.
Brown, GP,
and
Venuto RC.
Angiotensin II receptor alterations during pregnancy in the rabbit.
Am J Physiol Endocrinol Metab
251:
E58-E64,
1986
16.
Bunn, SJ,
and
Marley PD.
Effects of angiotensin II on cultured, bovine adrenal medullary cells.
Neuropeptides
13:
121-132,
1989[Web of Science][Medline].
17.
Burrell, JH,
and
Lumbers ER.
Angiotensin receptor subtypes in the uterine artery during ovine pregnancy.
Eur J Pharmacol
330:
257-267,
1997[Web of Science][Medline].
18.
Campbell, WB,
and
Jackson EK.
Modulation of adrenergic transmission by angiotensin in the perfused rat mesentery.
Am J Physiol Heart Circ Physiol
236:
H211-H217,
1979.
19.
Chen, L,
McNeill JR,
Wilson TW,
and
Copolakrishnan V.
Heterogenicity in vascular smooth muscle responsiveness to angiotensin II. Role of endothelin.
Hypertension
26:
83-88,
1995
20.
Chesley, LC,
Talledo E,
Bohler CS,
and
Zuspan FP.
Vascular reactivity to angiotensin II and norepinephrine in pregnant and nonpregnant women.
Am J Obstet Gynecol
91:
837-842,
1965[Web of Science][Medline].
21.
Chiu, AT,
Roscoe WA,
McCall DE,
and
Timmermans PBMWM
Angiotensin II-1 receptors mediate both vasoconstrictor and hypertrophic responses in rat aortic smooth muscle cells.
Receptor
1:
133-140,
1991[Medline].
22.
Cipolla, M,
and
Oslo G.
Hypertrophic and hyperplastic effects of pregnancy on the rat uterine arterial wall.
Am J Obstet Gynecol
171:
805-811,
1994[Web of Science][Medline].
23.
Cipolla, MJ,
Binder ND,
and
Osol G.
Myoendometrial versus placental uterine arteries: structural, mechanical, and functional differences in late-pregnant rabbits.
Am J Obstet Gynecol
177:
215-221,
1997[Web of Science][Medline].
24.
Clark, KE,
Austin JE,
and
Seeds AE.
Effect of bisenoic prostaglandins and arachidonic acid on the uterine vasculature of pregnant sheep.
Am J Obstet Gynecol
142:
261-268,
1982[Web of Science][Medline].
25.
Clark, KE,
Austin JE,
and
Stys SJ.
The effect of bisenoic prostaglandins on the uterine vasculature of the nonpregnant sheep.
Prostaglandins
22:
333-348,
1981[Web of Science][Medline].
26.
Clark, KE,
Iron GL,
and
Mack CE.
Differential responses of uterine and umbilical vasculatures to angiotensin II and norepinephrine.
Am J Physiol Heart Circ Physiol
259:
H197-H203,
1990
27.
Clark, KE,
Ryan MJ,
and
Brody MJ.
Effect of prostaglandins on vascular resistance and adrenergic vasoconstrictor responses in the canine uterus.
Prostaglandins
12:
71-82,
1976[Web of Science][Medline].
28.
Cohen, DM,
Steinberger SJ,
Swan JF,
and
Disalvo J.
Angiotensin II increases uterine vascular resistance in pregnant and non-pregnant rabbits.
Proc Soc Exp Biol Med
154:
597-601,
1977[Medline].
29.
Conrad, KP,
and
Colpoys MC.
Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy.
J Clin Invest
77:
236-245,
1986.
30.
Cox, BE,
Ipson MA,
Shaul PW,
Kamm KE,
and
Rosenfeld CR.
Myometrial angiotensin II receptor subtypes change during ovine pregnancy.
J Clin Invest
92:
2240-2248,
1993.
31.
Cox, BE,
and
Rosenfeld CR.
Ontogeny of vascular angiotensin II receptor subtype expression in ovine development.
Pediatr Res
45:
414-424,
1999[Web of Science][Medline].
32.
Cox, BE,
Rosenfeld CR,
Kalinyak JE,
Magness RR,
and
Shaul PW.
Tissue specific expression of vascular smooth muscle angiotensin II receptor subtypes during ovine pregnancy.
Am J Physiol Heart Circ Physiol
271:
H212-H221,
1996
33.
Cox, BE,
Roy TA,
and
Rosenfeld CR.
Uteroplacental vascular responses to systemic angiotensin II reflect catecholamine release, while pressure responses are due to A II receptor type 1 stimulation (Abstract).
J Soc Gynecol Investig
5:
144A,
1998.
34.
Cox, BE,
Williams CE,
and
Rosenfeld CR.
Angiotensin II indirectly vasoconstricts the ovine uterine circulation.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R337-R344,
2000
35.
Cox, BE,
Word RA,
and
Rosenfeld CR.
Angiotensin II receptor characteristics and subtype expression in uterine arteries and myometrium during pregnancy.
J Clin Endocrinol Metab
81:
49-58,
1996[Abstract].
36.
Cunningham, FG,
MacDonald PC,
and
Gant NF.
Maternal adaptations to pregnancy.
In: Williams Obstetrics (18th ed.), edited by Cunningham FG,
MacDonald PC,
and Gant NF.. Norwalk, CT: Appleton & Lange, 1989, p. 129-162.
37.
Curran-Everett, D,
Morris KG, Jr,
and
Moore LG.
Regional circulatory contributions to increased systemic vascular conductance of pregnancy.
Am J Physiol Heart Circ Physiol
261:
H1842-H1847,
1991
38.
Davis, LE,
Magness RR,
and
Rosenfeld CR.
Role of angiotensin II and
-adrenergic receptors during estrogen-induced vasodilation in ewes.
Am J Physiol Endocrinol Metab
263:
E837-E843,
1992.
39.
Dijkhorst-Oei, LT,
Stroes ESG,
Koomans HA,
and
Rabelink TJ.
Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo.
J Cardiovasc Pharmacol
33:
420-424,
1999[Web of Science][Medline].
40.
Donato, L,
Coli A,
Pasqualini R,
and
Duce T.
Metabolic clearance rate of radioiodinated angiotensin II in normal men.
Am J Physiol
223:
1250-1256,
1972.
41.
Douglas, JR, Jr,
Johnson EM, Jr,
Marshall GR,
Jaffe BM,
and
Needleman P.
Stimulation of splenic prostaglandin release by angiotensin and specific inhibition by cystine8-AII.
Prostaglandins
3:
67-74,
1973[Web of Science][Medline].
42.
Doyle, AE,
Louis WJ,
Jerums G,
and
Osborn EC.
Metabolism and blood levels following infusion of a radioactive analog of angiotensin.
Am J Physiol
215:
164-168,
1968.
43.
Dudley, DT,
Panek RL,
Major TC,
Lu GH,
Bruns RF,
Klinkefus BA,
Hodges JC,
and
Weishaar RE.
Subclasses of angiotensin II binding sites and their functional significance.
Mol Pharmacol
38:
370-377,
1990[Abstract].
44.
Erkkola, RU,
and
Pirhonen JP.
Flow velocity waveforms in uterine and umbilical arteries during the angiotensin II sensitivity test.
Am J Obstet Gynecol
162:
1193-1197,
1990[Web of Science][Medline].
45.
Erkkola, RU,
and
Pirhonen JP.
Uterine and umbilical flow velocity waveforms in normotensive and hypertensive subjects during the angiotensin II sensitivity test.
Am J Obstet Gynecol
166:
910-916,
1992[Web of Science][Medline].
46.
Fei, DTW,
Coghlan JP,
Fernley RT,
and
Scoggins BA.
Blood clearance rates of angiotensin II and its metabolites in sheep: presence of immunoreactive fragments in arterial blood.
Clin Exp Pharmacol Physiol
6:
129-137,
1979[Web of Science][Medline].
47.
Fei, DTW,
Scoggins BA,
Tregear GW,
and
Coghlan JP.
Reduction of blood clearance rate of [Val5]angiotensin II by [Sar1, Ile8]angiotensin II in sheep.
Life Sci
29:
157-163,
1981[Web of Science][Medline].
48.
Ferris, TF,
Stein JH,
and
Kaufman J.
Uterine blood flow and uterine renin secretion.
J Clin Invest
51:
2827-2833,
1972.
49.
Gant, NF, Jr,
Daley GL,
Chand S,
Whalley PJ,
and
MacDonald PC.
A study of angiotensin II pressor responses throughout primigravid pregnancy.
J Clin Invest
52:
2682-2689,
1973.
50.
Glance, DG,
Elder MG,
and
Myatt L.
Prostaglandin production and stimulation by angiotensin II in the isolated perfused human placental cotyledon.
Am J Obstet Gynecol
151:
387-391,
1985[Web of Science][Medline].
51.
Godard, C,
Gaillard R,
and
Vallotton MB.
The renin-angiotensin system in mother and fetus at term.
Nephron
17:
353-360,
1976[Web of Science][Medline].
52.
Goodman, RP,
Killam AP,
Brash AR,
and
Branch RA.
Prostacyclin production during pregnancy: comparison of production during normal pregnancy and pregnancy complicated by hypertension.
Am J Obstet Gynecol
142:
817-822,
1982[Web of Science][Medline].
53.
Gough, ED,
and
Dyer DC.
Responses of isolated human uterine arteries to vasoactive drugs.
Am J Obstet Gynecol
110:
625-629,
1971[Web of Science][Medline].
54.
Grady, EF,
Sechi LA,
Griffin CA,
Schambelan M,
and
Kalinyak JE.
Expression of AT2 receptors in the developing rat fetus.
J Clin Invest
88:
921-933,
1991.
55.
Greiss, FC,
Anderson SG,
and
Still JG.
Uterine pressure-flow relationships during early gestation.
Am J Obstet Gynecol
126:
799-805,
1976[Web of Science][Medline].
56.
Greiss, FC, Jr,
and
VanWilkes D.
Effects of sympathomimetic drugs and angiotensin on the uterine vascular bed.
Obstet Gynecol
23:
925-930,
1964[Web of Science][Medline].
57.
Griendling, KK,
Fuller EO,
and
Cox RH.
Pregnancy-induced changes in sheep uterine and carotid arteries.
Am J Physiol Heart Circ Physiol
248:
H658-H665,
1985.
58.
Hagemann, A.
Solution of methodological problems in prorenin measurement and investigations of tissue renin-angiotensin systems in the female reproductive tract.
Dan Med Bull
44:
486-488,
1997[Web of Science][Medline].
59.
Harrison, GL,
and
Moore LG.
Blunted vasoreactivity in pregnant guinea pigs is not restored by meclofenamate.
Am J Obstet Gynecol
160:
258-264,
1989[Web of Science][Medline].
60.
Inagami, T,
Gero DF,
and
Kitami Y.
Molecular biology of angiotensin II receptors: an overview.
J Hypertens
12:
S83-S94,
1994[Web of Science].
61.
Iwai, N,
and
Inagami T.
Identification of two subtypes in the rat type 1 angiotensin II receptor.
FEBS Lett
298:
257-260,
1992[Web of Science][Medline].
62.
Iyer, SN,
Chappell MC,
Brosnihan KB,
and
Ferrario CM.
Role of AT1 and AT2 receptors in the plasma clearance of angiotensin II.
J Cardiovasc Pharmacol
31:
464-469,
1998[Web of Science][Medline].
63.
Janowiak, MA,
Magness RR,
Habermehl DA,
and
Bird IM.
Pregnancy increases ovine uterine artery endothelial cyclooxygenase-1 expression.
Endocrinology
139:
765-771,
1998
64.
Johnson, AR,
Skidgel RA,
Gafford JT,
and
Erdas EG.
Enzymes in placental microvilli: angiotensin I converting enzyme, angiotensinase A, carboxypeptidases, and neutral endopeptidase (enkephalinase).
Peptides
5:
789-796,
1984[Web of Science][Medline].
65.
Johnson, CI,
Mendelsohn FAO,
and
Doyle AE.
Metabolism of angiotensin II in sodium depletion and hypertension in humans.
Circ Res
31, Suppl30:
203-213,
1972.
66.
Keyes, LE,
Majack R,
Dempsey EC,
and
Moore LG.
Pregnancy stimulation of DNA synthesis and uterine blood flow in the guinea pig.
Pediatr Res
41:
708-715,
1997[Web of Science][Medline].
67.
Keyes, LE,
Moore LG,
Walchak SJ,
and
Dempsey EC.
Pregnancy-stimulated growth of vascular smooth muscle cells: importance of protein kinase C-dependent synergy between estrogen and platelet-derived growth factor.
J Cell Physiol
166:
22-32,
1996[Web of Science][Medline].
68.
Kurauchi, O,
Mizutani S,
Nomura S,
Furuhashi M,
Kasugai M,
and
Tomoda Y.
Changes in the binding of angiotensin II to rat placental receptors by estrogen and progesterone.
Horm Metab Res
21:
558-560,
1989[Web of Science][Medline].
69.
Ladner, C,
Brinkman CR,
Weston P,
and
Assali NS.
Dynamics of uterine circulation in pregnant and nonpregnant sheep.
Am J Physiol
218:
257-263,
1970.
70.
Laird, MR,
Faber JJ,
and
Binder ND.
Maternal placental blood flow is reduced in proportion to reduction in uterine driving pressure.
Pediatr Res
36:
102-110,
1994[Web of Science][Medline].
71.
Lambers, DS,
Greenberg SG,
and
Clark KE.
Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep.
Am J Physiol Heart Circ Physiol
278:
H353-H359,
2000
72.
Landauer, M,
Phernetton TM,
Parisi VM,
Clark RE,
and
Rankin JHG
Ovine placental vascular response to the local application of prostacyclin.
Am J Obstet Gynecol
151:
460-464,
1984[Web of Science].
73.
Leary, WP,
and
Ledingham JG.
Inactivation of angiotensin II analogues by isolated perfused rat liver and kidney.
Nature
227:
178-179,
1970[Medline].
74.
Lubarsky, SL,
Ahokas RA,
Friedman SA,
and
Sibai BM.
The effect of chronic nitric oxide synthesis inhibition on blood pressure and angiotensin II responsiveness in the pregnant rat.
Am J Obstet Gynecol
176:
1069-1076,
1997[Web of Science][Medline].
75.
Lumbers, ER,
and
Reid GC.
The actions of vasoactive compounds in the foetus and the effect of perfusion through the placenta on their biological activity.
Austral J Exp Biol Med Sci
56:
11-24,
1978[Web of Science][Medline].
76.
Mackanjee, HR,
Shaul PW,
Magness RR,
and
Rosenfeld CR.
Angiotensin II vascular smooth muscle receptors are not down-regulated in near-term pregnant sheep.
Am J Obstet Gynecol
165:
1641-1648,
1991[Web of Science][Medline].
77.
Magness, RR,
Cox K,
Rosenfeld CR,
and
Gant NF.
Angiotensin II metabolic clearance rate and pressor responses in nonpregnant and pregnant women.
Am J Obstet Gynecol
171:
668-679,
1994[Web of Science][Medline].
78.
Magness, RR,
Mitchell MD,
and
Rosenfeld CR.
Uteroplacental production of eicosanoids in ovine pregnancy.
Prostaglandins
39:
75-88,
1990[Web of Science][Medline].
79.
Magness, RR,
Osei-Boaten K,
Mitchell MD,
and
Rosenfeld CR.
In vitro prostacyclin production by ovine uterine and systemic arteries: effects of angiotensin II.
J Clin Invest
76:
2206-2212,
1985.
80.
Magness, RR,
Parker CR, Jr,
and
Rosenfeld CR.
Systemic and uterine responses to chronic infusion of estradiol-17.
Am J Physiol Endocrinol Metab
265:
E690-E698,
1993
81.
Magness, RR,
and
Rosenfeld CR.
Systemic and uterine responses to
-adrenergic stimulation in pregnant and nonpregnant ewes.
Am J Obstet Gynecol
155:
897-904,
1986[Web of Science][Medline].
82.
Magness, RR,
and
Rosenfeld CR.
Eicosanoids and the regulation of uteroplacental hemodynamics.
In: Eicosanoids in Reproduction, edited by Mitchell MD.. Boca Raton, FL: CRC, 1990, p. 139-162.
83.
Magness, RR,
and
Rosenfeld CR.
Calcium modulation of endothelium-derived prostacyclin in ovine pregnancy.
Endocrinology
132:
2445-2452,
1993
84.
Magness, RR,
Rosenfeld CR,
Faucher DJ,
and
Mitchell MD.
Uterine prostaglandin production in ovine pregnancy: effects of angiotensin II and indomethacin.
Am J Physiol Heart Circ Physiol
263:
H188-H197,
1992
85.
Magness, RR,
Rosenfeld CR,
Hassan A,
and
Shaul PW.
Endothelial vasodilator production by uterine and systemic arteries. I Effects of ANG II on PGI2 and NO in pregnancy.
Am J Physiol Heart Circ Physiol
270:
H1914-H1923,
1996
86.
Magness, RR,
Shaw CE,
Pernetton TM,
Zheng J,
and
Bird IM.
Endothelial vasodilator production of uterine and systemic arteries. II Pregnancy effects on NO synthase expression.
Am J Physiol Heart Circ Physiol
272:
H1730-H1740,
1997
87.
Makowski, EL,
Meschia G,
Droegenmueller W,
and
Battaglia FC.
Distribution of uterine blood flow in the pregnant sheep.
Am J Obstet Gynecol
101:
409-412,
1968[Web of Science][Medline].
88.
McGiff, JC,
Crowshaw K,
Terragno NA,
and
Lonigro AJ.
Release of a prostaglandin-like substance into renal venous blood in response to angiotensin II.
Circ Res
26, SupplI:
121-130,
1970.
89.
McLaughlin, MK,
Brennen SC,
and
Chez RA.
Effects of indomethacin on sheep utero-placental circulations and sensitivity to angiotensin II.
Am J Obstet Gynecol
132:
430-435,
1978[Web of Science][Medline].
90.
McMullen, JR,
Gibson KJ,
Lumbers ER,
Burrell LH,
and
Wu J.
Interactions between AT1 and AT2 receptors in uterine arteries from pregnant ewes.
Eur J Pharmacol
378:
195-202,
1999[Web of Science][Medline].
91.
Metcalf, J,
and
Parer JT.
Cardiovascular changes during pregnancy in ewes.
Am J Physiol
210:
821-825,
1966.
92.
Mitzutani, S,
and
Tomoda Y.
Oxytocinase: placental cystine aminopeptidase or placental leucine aminopeptidase (P-LAP).
Semin Reprod Endocrinol
10:
146-153,
1992.
93.
Naden, RP,
Coultrup S,
Arant BS, Jr,
and
Rosenfeld CR.
Metabolic clearance of angiotensin II in pregnant and nonpregnant sheep.
Am J Physiol Endocrinol Metab
249:
E49-E55,
1985
94.
Naden, RP,
Iliya CA,
Arant BS, Jr,
Gant NF, Jr,
and
Rosenfeld CR.
Hemodynamic effects of indomethacin in chronically instrumented pregnant sheep.
Am J Obstet Gynecol
151:
484-494,
1985[Web of Science][Medline].
95.
Naden, RP,
and
Rosenfeld CR.
Effect of angiotensin II on uterine and systemic vasculature in pregnant sheep.
J Clin Invest
68:
468-474,
1981.
96.
Naden, RR,
and
Rosenfeld CR.
Systemic and uterine responsiveness to angiotensin II and norepinephrine in estrogen-treated nonpregnant sheep.
Am J Obstet Gynecol
153:
417-425,
1985[Web of Science][Medline].
97.
Nathan, L,
Cuevas J,
and
Chandhuri G.
The role of nitric oxide in the altered vascular reactivity of pregnancy in the rat.
Br J Pharmacol
114:
955-960,
1995[Web of Science][Medline].
98.
Novy, MJ,
Thomas CL,
and
Lees MH.
Uterine contractility and regional blood flow responses to oxytocin and prostaglandin E2 in pregnant rhesus monkey.
Am J Obstet Gynecol
122:
419-433,
1975[Web of Science][Medline].
99.
Nunotani, T,
Matsuura S,
Tamai T,
Tatsumi N,
Sagawa N,
and
Mori T.
The response to isolated uterine arteries from pregnant sows to vasoconstrictive agents.
Acta Obst Gynaec Jpn
37:
15-23,
1985.
100.
Oelkers, W,
Dusterdieck G,
and
Morton JJ.
Arterial angiotensin II and venous immunoreactive material before and during angiotensin infusion in man.
Clin Sci (Colch)
43:
209-218,
1972[Web of Science][Medline].
101.
Osol, G,
and
Cipolla M.
Pregnancy-induced changes in the three-dimensional mechanical properties of pressurized rat uteroplacental (radial) arteries.
Am J Obstet Gynecol
168:
268-274,
1993[Web of Science][Medline].
102.
Owens, GK.
Control of hypertrophic versus hyperplastic growth of vascular smooth muscle cells.
Am J Physiol Heart Circ Physiol
257:
H1755-H1765,
1989
103.
Page, EW.
Plasma angiotonase concentration in normal and toxemic pregnancies.
Am J Med Sci
213:
715-718,
1947[Web of Science].
104.
Paller, MS.
Mechanism of decreased pressor responsiveness to ANG II, NE, and vasopressin in pregnant rats.
Am J Physiol Heart Circ Physiol
247:
H100-H108,
1984.
105.
Parent, A,
Schiffrin EL,
and
St-Louis J.
Receptors for Arg8-vasopressin, angiotensin II, and atrial natriuretic peptide in the mesenteric vasculature of pregnant rats.
Can J Physiol
69:
137-144,
1991[Web of Science][Medline].
106.
Peach, MJ,
Cline WH, Jr,
and
Watts DT.
Release of adrenal catecholamines by angiotensin II.
Circ Res
19:
571-575,
1966
107.
Perales, AJ,
Naden RP,
Laptook AR,
and
Rosenfeld CR.
Fetal responses to maternal infusions of angiotensin II.
Am J Obstet Gynecol
154:
195-203,
1986[Web of Science][Medline].
108.
Peters, LLH,
Sparks JW,
Grutters G,
Girard J,
and
Battaglia FC.
Uteroplacental blood flow during pregnancy in chronically catheterized guinea pigs.
Pediatr Res
16:
716-720,
1982[Web of Science][Medline].
109.
Pipkin, FB,
and
O'Brien PMS
Effect of the specific angiotensin antagonist (Sar1) (Ala8) angiotensin II on blood pressure and the renin-angiotensin system in the conscious pregnant ewe and fetus.
Am J Obstet Gynecol
132:
7-15,
1978[Web of Science][Medline].
110.
Poulsen, H,
Sjoberg NO,
Stjernquist M,
and
Zia E.
Atrial natriuretic peptide antagonizes the contractile effect of angiotensin II in the human uterine artery.
Hum Reprod
9:
1939-1943,
1994
111.
Rankin, JHG,
Phernetton TM,
Anderson DF,
and
Berssenbrugge AD.
Effect of prostaglandin I2 on ovine placental vasculature.
J Dev Physiol
1:
151-160,
1979[Medline].
112.
Rankin, JHG,
and
Phernetton TM.
Effect of prostaglandin E2 on ovine maternal placental blood flow.
Am J Physiol
231:
754-759,
1976.
113.
Reynolds, LP,
and
Redmen DA.
Utero-placental vascular development and placental function.
J Anim Sci
73:
1839-1851,
1995[Abstract].
114.
Rosenfeld, CR.
Distribution of cardiac output in ovine pregnancy.
Am J Physiol Heart Circ Physiol
232:
H231-H235,
1977.
115.
Rosenfeld, CR.
Consideration of the uteroplacental circulation in intrauterine growth.
Semin Perinatol
8:
42-51,
1984[Web of Science][Medline].
116.
Rosenfeld, CR.
The Uterine Circulation. Ithaca, NY: Perinatology Press, 1989.
117.
Rosenfeld, CR,
Barton MD,
and
Meschia G.
Effects of epinephrine on distribution of blood flow in the pregnant ewe.
Am J Obstet Gynecol
124:
156-163,
1976[Web of Science][Medline].
118.
Rosenfeld, CR,
Cox BE,
Magness RR,
and
Shaul PW.
Ontogeny of angiotensin II vascular smooth muscle receptors in ovine fetal aorta and placental and uterine arteries.
Am J Obstet Gynecol
168:
1562-1569,
1993[Web of Science][Medline].
119.
Rosenfeld, CR,
Cox BE,
Roy T,
and
Magness RR.
Nitric oxide contributes to estrogen-induced vasodilation of ovine uterine circulation.
J Clin Invest
98:
2158-2166,
1996[Web of Science][Medline].
120.
Rosenfeld, CR,
and
Gant NF, Jr.
The chronically instrumented ewe. A model for studying vascular reactivity to angiotensin II in pregnancy.
J Clin Invest
67:
486-492,
1981.
121.
Rosenfeld, CR,
Gresores A,
Roy TA,
and
Magness RR.
Comparison of ANG II in fetal and pregnant sheep: metabolic clearance and vascular sensitivity.
Am J Physiol Endocrinol Metab
268:
E237-E247,
1995
122.
Rosenfeld, CR,
and
Jackson GM.
Estrogen-induced refractoriness to the pressor effects of infused angiotensin II.
Am J Obstet Gynecol
148:
429-435,
1984[Web of Science][Medline].
123.
Rosenfeld, CR,
Killam AP,
Battaglia FC,
Makowski EL,
and
Meschia G.
Effect of estradiol-17
on the magnitude and distribution of uterine blood flow in nonpregnant, oophorectomized ewes.
Pediatr Res
7:
139-148,
1973.
124.
Rosenfeld, CR,
Morris FH, Jr,
Makowski EL,
Meschia G,
and
Battaglia FC.
Circulatory changes in the reproductive tissues of ewes during pregnancy.
Gynecol Invest
5:
252-268,
1974[Web of Science][Medline].
125.
Rosenfeld, CR,
and
Naden RP.
Uterine and nonuterine vascular responses to angiotensin II in ovine pregnancy.
Am J Physiol Heart Circ Physiol
257:
H17-H24,
1989
126.
Rosenfeld, CR,
and
West JA.
Circulatory responses to systemic infusions of norepinephrine in the pregnant ewe.
Am J Obstet Gynecol
27:
376-383,
1977.
127.
Salhab, WA,
Shaul PW,
Cox BE,
and
Rosenfeld CR.
Regulation of types I and III NOS in ovine uterine arteries by daily and acute estrogen exposure.
Am J Physiol Heart Circ Physiol
278:
H2134-H2142,
2000
128.
Schirar, A,
Capponi A,
and
Catt KJ.
Regulation of uterine angiotensin II receptors by estrogen and progesterone.
Endocrinology
106:
5-12,
1980
129.
Schobel, HP,
Fischer T,
Heuszer K,
Geiger H,
and
Schmieder RE.
Preeclampsia-A state of sympathetic over reactivity.
N Engl J Med
335:
1480-1485,
1996
130.
Searles, CD,
and
Harrison DG.
The interaction of nitric oxide, bradykinin and the angiotensin II type 2 receptor: lessons learned from transgenic mice.
J Clin Invest
104:
1013-1014,
1999[Web of Science][Medline].
131.
Siddiqi, TA,
Koenig BB,
and
Clark KE.
Pregnancy causes a decrease in the number and affinity of myometrial angiotensin II receptors.
Obstet Gynecol
68:
820-824,
1986[Web of Science][Medline].
132.
Skinner, SL,
Lumbers ER,
and
Symonds EM.
Analysis of changes in the renin-angiotensin system during pregnancy.
Clin Sci (Colch)
42:
479-488,
1972[Web of Science][Medline].
133.
Sladek, SM,
Magness RR,
and
Conrad KP.
Nitric oxide and pregnancy.
Am J Physiol Regulatory Integrative Comp Physiol
272:
R441-R463,
1997
134.
Speroff, L,
Hunting RV,
and
Levin RM.
The effect of angiotensin II and indomethacin on uterine artery blood flow in pregnant monkeys.
Obstet Gynecol
50:
611-614,
1977[Web of Science][Medline].
135.
Stanley, JR,
Giammattei CE,
Sheikh AU,
Green JL,
Zehnder T,
and
James Rose C.
Effects of chronic infusion of angiotensin II on renin and blood pressure in the late-gestation fetal sheep.
Am J Obstet Gynecol
176:
931-937,
1997[Web of Science][Medline].
136.
St. Louis, J,
Pare H,
Sicotte B,
and
Brochu M.
Increased reactivity of rat uterine arcuate artery throughout gestation and postpartum.
Am J Physiol Heart Circ Physiol
273:
H1148-H1153,
1997
137.
Symonds, EM.
The placenta and the renin-angiotensin system.
J Reprod Med
23:
129-133,
1979[Web of Science][Medline].
138.
Symonds, EM.
Renin and reproduction.
Am J Obstet Gynecol
158:
754-760,
1988[Web of Science][Medline].
139.
Symons, JD,
Musch TI,
Hageman KS,
and
Stebbins CL.
Regional blood flow responses to acute ANG II infusion: effects of nitric oxide synthase inhibition.
J Cardiovasc Pharmacol
34:
116-123,
1999[Web of Science][Medline].
140.
Talledo, OE.
Renin-angiotensin system in normal and toxemic pregnancies. II. Inactivation of angiotensin in normal pregnancy.
Am J Obstet Gynecol
97:
571-572,
1967[Web of Science][Medline].
141.
Talledo, OE,
Chesley LC,
and
Zuspan FP.
Renin-angiotensin system in normal and toxemic pregnancies. III Differential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy.
Am J Obstet Gynecol
100:
218-221,
1968[Web of Science].
142.
Terragno, NA,
Terragno DA,
Pacholczyk D,
and
McGiff JC.
Prostaglandins and the regulation of uterine blood flow in pregnancy.
Nature
249:
57-58,
1974[Medline].
143.
Thaler, I,
Manor D,
Itskovitz J,
Rottem S,
Levit N,
Timor-Tritsch I,
and
Brandes JM.
Changes in uterine blood flow during human pregnancy.
Am J Obstet Gynecol
162:
121-125,
1990[Web of Science][Medline].
144.
Tsatsumi, Y,
Matsubara H,
Masaki H,
Kurihara H,
Murasawa S,
Takai S,
Miyazaki M,
Nozawa Y,
Ozono R,
Nakagawa K,
Miwa T,
Kawada N,
Mori Y,
Shibasaki Y,
Tanaka Y,
Fujiyama S,
Koyama Y,
Fujiyama A,
Takahashi H,
and
Iwasaka T.
Angiotensin II type 2 receptor over expression activates the vascular renin system and causes vasodilation.
J Clin Invest
104:
925-935,
1999[Web of Science][Medline].
145.
Tsutsumi, K,
and
Saavedra JM.
Characterization of AT2 angiotensin II receptors in rat anterior cerebral arteries.
Am J Physiol Heart Circ Physiol
261:
H667-H670,
1991
146.
Vagnoni, KE,
Shaw CE,
Phernetton TM,
Meglin BM,
Bird IM,
and
Magness RR.
Endothelial vasodilator production by uterine and systemic arteries. III. Ovarian and estrogen effects on NO synthase.
Am J Physiol Heart Circ Physiol
275:
H1845-H1856,
1998
147.
Van Buren, GA,
Yang D,
and
Clark KE.
Estrogen-induced uterine vasodilation is antagonized by L-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis.
Am J Obstet Gynecol
167:
828-833,
1992[Web of Science][Medline].
148.
Venuto, RC,
Cox JW,
Stein JH,
and
Ferris TF.
The effect of changes in perfusion pressure on uteroplacental blood flow in the pregnant rabbit.
J Clin Invest
57:
938-944,
1976.
149.
Venuto, RC,
O'Dorisio T,
Stein JH,
and
Ferris TF.
Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit.
J Clin Invest
55:
193-197,
1975.
150.
Viswanathan, M,
Tsutsumi K,
Correa FMA,
and
Saavedra JM.
Changes in expression of angiotensin receptor subtypes in the rat aorta during development.
Biochem Biophys Res Commun
179:
1361-1367,
1991[Web of Science][Medline].
151.
Weiner, CP,
Hdez M,
Chestnut DH,
and
Herrig J.
Effect of exogenous prostacyclin on central and uterine hemodynamics in the chronically instrumented pregnant guinea pig before and after indomethacin administration.
Am J Obstet Gynecol
160:
489-493,
1989[Web of Science][Medline].
152.
Woods, L.
Role of angiotensin II and prostaglandins in the regulation of uteroplacental blood flow.
Am J Physiol Regulatory Integrative Comp Physiol
264:
R584-R590,
1993
153.
Worley, RJ,
Grant NF, Jr,
Everett RB,
and
MacDonald PC.
Vascular responsiveness to pressor agents during human pregnancy.
J Reprod Med
23:
115-128,
1979[Web of Science][Medline].
154.
Xiao, D,
Lin Y.,
Pearce WJ,
and
Zhang L.
Endothelial nitric oxide release in isolated perfused ovine uterine arteries: effect of pregnancy.
Eur J Pharmacol
367:
223-230,
1999[Web of Science][Medline].
155.
Yang, CCH,
Chao TC,
Kuo TBJ,
Yin CS,
and
Chen HI.
Preeclamptic pregnancy is associated with increased sympathetic and decreased parasympathetic control of HR.
Am J Physiol Heart Circ Physiol
278:
H1269-H1273,
2000
156.
Yoshimura, T,
Rosenfeld CR,
and
Magness RR.
Angiotensin II and
-agonist. III In vitro fetal-maternal placental prostaglandins.
Am J Physiol Endocrinol Metab
260:
E8-E13,
1991
157.
Zwart, AS,
Davis EA,
and
Widdop RE.
Modulation of AT1 receptor-mediated contraction of rat uterine artery by AT2 receptors.
Br J Pharmacol
125:
1429-1436,
1998[Web of Science][Medline].
This article has been cited by other articles:
![]() |
C. R. Rosenfeld, X.-t. Liu, and K. DeSpain Pregnancy modifies the large conductance Ca2+-activated K+ channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1878 - H1887. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Osol and M. Mandala Maternal Uterine Vascular Remodeling During Pregnancy Physiology, February 1, 2009; 24(1): 58 - 71. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. S. Gilbert, B. B. LaMarca, and J. P. Granger ACE2 and ANG-(1-7) in the gravid uterus: the new players on the block Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R915 - R916. [Full Text] [PDF] |
||||
![]() |
H. Zhang and L. Zhang Role of Protein Kinase C Isozymes in the Regulation of alpha1-Adrenergic Receptor-Mediated Contractions in Ovine Uterine Arteries Biol Reprod, January 1, 2008; 78(1): 35 - 42. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Maduwegedera, M. M. Kett, R. L. Flower, G. W. Lambert, J. F. Bertram, E. M. Wintour, and K. M. Denton Sex differences in postnatal growth and renal development in offspring of rabbit mothers with chronic secondary hypertension Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R706 - R714. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Zhang, D. Xiao, L. D. Longo, and L. Zhang Regulation of {alpha}1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2282 - H2289. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Xiao, X. Huang, L. D. Longo, W. J. Pearce, and L. Zhang Regulation of baseline Ca2+ sensitivity in permeabilized uterine arteries: effect of pregnancy Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H413 - H420. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Nagar, X.-t. Liu, and C. R. Rosenfeld Estrogen regulates {beta}1-subunit expression in Ca2+-activated K+ channels in arteries from reproductive tissues Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1417 - H1427. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. R. Rosenfeld, T. Roy, K. DeSpain, and B. E. Cox Large-Conductance Ca2+-Dependent K+ Channels Regulate Basal Uteroplacental Blood Flow in Ovine Pregnancy Reproductive Sciences, September 1, 2005; 12(6): 402 - 408. [Abstract] [PDF] |
||||
![]() |
B. E. Cox, T. A. Roy, and C. R. Rosenfeld Angiotensin II mediates uterine vasoconstriction through {alpha}-stimulation Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H126 - H134. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. B. Persson, A. Skalweit, R. Mrowka, and B.-J. Thiele Control of renin synthesis Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R491 - R497. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. P. Granger Maternal and fetal adaptations during pregnancy: lessons in regulatory and integrative physiology Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2002; 283(6): R1289 - R1292. [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |