Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy
Eugenie R. Lumbers and Kirsty G. Pringle
School of Biomedical Sciences and Pharmacy and Mothers and Babies Research Centre, Hunter Medical Research Institute,
University of Newcastle, Newcastle, New South Wales, Australia
Submitted 24 January 2013; accepted in final form 2 October 2013
Lumbers ER, Pringle KG. The roles of the circulating renin-angiotensin-aldosterone
system in human pregnancy. Am J Physiol Regul Integr Comp Physiol 306: R91–R101,
2014. First published October 2, 2013; doi:10.1152/ajpregu.00034.2013.—This review
describes the changes that occur in circulating renin-angiotensin-aldosterone sys-
tem (RAAS) components in human pregnancy. These changes depend on endo-
crine secretions from the ovary and possibly the placenta and decidua. Not only do
these hormonal secretions directly contribute to the increase in RAAS levels, they
also cause physiological changes within the cardiovascular system and the kidney,
which, in turn, induce reflex release of renal renin. High levels of ANG II play a
critical role in maintaining circulating blood volume, blood pressure, and uteropla-
cental blood flow through interactions with the ANG II type I receptor and through
increased production of downstream peptides acting on a changing ANG receptor
phenotype. The increase in ANG II early in gestation is driven by estrogen-induced
increments in angiotensinogen (AGT) levels, so there cannot be negative feedback
leading to reduced ANG II production. AGT can exist in various forms in terms of
redox state or complexed with other proteins as polymers; these affect the ability of
renin to cleave ANG I from AGT. Thus, during pregnancy the rate of ANG I
production varies not only because levels of renin change in response to homeo-
static demand but also because AGT changes not only in concentration but in form.
Activation of the circulating and intrarenal RAASs is essential for normal preg-
nancy outcome subserving the increased demand for salt and, hence, water during
pregnancy. Thus, the complex integration of the secretions and actions of the
circulating maternal renin-angiotensin system in pregnancy plays a key role in
pregnancy outcome.
renin-angiotensin-aldosterone system; pregnancy; fluid and electrolyte balance;
renal function; circulation
IN HUMAN PREGNANCY, THE MATERNAL and fetal circulating renin-
angiotensin-aldosterone systems (RAAS) and various tissue
renin-angiotensin systems (RAS) interact to ensure a satisfac-
tory pregnancy outcome. Tissue RASs critically involved in
normal pregnancy are the ovarian, intrauterine (placental and
decidual), and the intrarenal RASs. The nonrenal RASs not
only play key roles in ovulation, implantation, placentation,
and development of the uteroplacental and umbilicoplacental
circulations, but they also contribute to the activity of the
circulating maternal RAAS, so influencing maternal cardiovas-
cular and renal function. The role of the maternal circulating
RAAS is the topic of this review. It should be appreciated that
the fetus also has a circulating functional renin-angiotensin
system, and this system together with its intrarenal RAS is
essential for normal renal development and function (33, 81).
The activity of the maternal circulating RAAS in pregnancy
does not solely depend on release of active renin from the
kidney. Although this source of renin is important, increased
production of angiotensinogen by the liver is also a major
influence. Its activity is also influenced at various stages of
gestation by contributions from the ovary and uteroplacental
unit. The actions of the maternal circulating RAAS are medi-
ated through various ANG peptides and receptors (see Fig. 1).
ANG II acting via the ANG II type 1 receptor (AT
1
R) is
predominantly vasoconstrictor; it is also a major regulator of
aldosterone secretion. There are additional actions of ANG II
mediated via an angiotensin type 2 receptor (AT
2
R) and of
other ANG peptides, in particular, ANG 1–7 via the Mas
receptor and ANG IV via AT
4
R. ANG IV can, however, also
act via AT1
a
R in the mouse kidney (88). These other ANG
peptides, which are also part of the circulating RAAS, and their
actions are also likely to contribute to pregnancy outcome.
This review describes our current understanding of the
circulating RAAS, how it changes during normal pregnancy,
and how it contributes to changes in cardiovascular and renal
function to maintain fluid and electrolyte balance and tissue
perfusion.
Circulating RAAS
The circulating RAAS is defined by the action of renin, a
36-kDa aspartyl protease, which cleaves a Val-Leu bond in a
large 62-kDa ␣2-globulin substrate, angiotensinogen (AGT), to
form ANG I. ANG I is converted to ANG II by angiotensin-
converting enzyme (ACE). ANG II is the major ANG peptide;
Address for reprint requests and other correspondence: Emeritus Scientia
Professor Eugenie R. Lumbers, School of Biomedical Sciences, Univ. of
Newcastle, Callaghan, Newcastle, NSW Australia, 2308 (e-mail: Eugenie.
Lumbers@newcastle.edu.au).
Am J Physiol Regul Integr Comp Physiol 306: R91–R101, 2014.
First published October 2, 2013; doi:10.1152/ajpregu.00034.2013.
Review
0363-6119/14 Copyright
©
2014 the American Physiological Societyhttp://www.ajpregu.org R91
its most well-described biological actions are mediated via the
AT
1
R, (Fig. 1A). Other ANG peptides in the circulation in
-
clude ANG (1–7), which is formed at the fastest rate from
ANG II (15, 64), ANG III, and ANG IV (Fig. 1B) (3, 15).
ANG II, as well as acting via its AT
1
R, can also bind to the
type 2 receptor, AT
2
R. Many actions of the ANG II/AT
2
R
interaction oppose the actions of ANG II/AT
1
R. Briefly, ANG
II/AT
1
R interactions cause vasoconstriction, aldosterone syn
-
thesis, secretion, angiogenesis, and cell proliferation. Those
mediated by ANG II/AT
2
R include vasodilatation and apopto
-
sis (15). ANG (1–7) acts via the MasR, a G protein-coupled
receptor (64), and many of its actions oppose the ANG II/
AT
1
R-induced effects, as do the actions of ANG IV mediated
via the AT
4
R, also known as IRAP [insulin regulated amino
-
peptidase (3)]. ANG IV/IRAP-induced effects include hyper-
trophy, vascularization, inflammation, and vasodilation (10), as
well as actions mediated via AT
1
Rs (88). IRAP has been
shown to be identical to placental oxytocinase (45).
The discovery of a precursor of active renin (now called
prorenin) many years ago (32) was initially regarded as of little
biological significance because prorenin, which has a 28-amino
acid prosequence that covers its catalytic site, was thought to
be biologically inactive. It could be shown to be activated in
vitro by low pH (32), cold, and proteases such as trypsin (44)
and cathepsin D (43). Even today, the biological significance of
“in vivo” proteolytic activation of prorenin, remains obscure
except for the specific proteolysis that occurs within the jux-
taglomerular cells lining the afferent arterioles of the kidney
that results in storage and release of active renin from these
cells into the blood.
In 2002, the biological significance of prorenin was realized
following the discovery of a prorenin receptor, (P)RR. The
45-kDa protein cloned by Nguyen et al. (49) is, in part,
identical to a 8.9-kDa truncated protein “M8 –9” that is copu-
rified with a vacuolar proton-ATPase, or V-ATPase. (P)RR
binds prorenin so that its catalytic site is exposed and ANG I
can be cleaved from AGT (49). There are three pathways via
which prorenin bound to (P)RR can have biological effects:
first by cleavage of ANG I from AGT, second by activation of
intracellular signaling [phosphorylation of ERK1/ERK2 or by
activation p27/HSP pathway (49, 66)] and third, through the
interaction of (P)RR with Wnt signaling pathways (48). The
fact that (P)RR knockouts are embryo-lethal indicates that
(P)RR plays an essential role in normal development.
A soluble form of (P)RR, s(P)RR, has also been described.
It is the 28-kDa portion of the receptor that is cleaved from the
M8 –9 component by the enzyme furin (48) and is found in the
circulation. Thus, circulating prorenin, which is much more
abundant in the blood than active renin and which increases to
very high levels early in pregnancy (Fig. 2A), is no longer
confined to the role of an inactive precursor of active renin. It
has its own biological activity, possibly as a circulating hor-
mone. s(P)RR may also be important in influencing the rate of
formation of ANG I from AGT in plasma and other bodily
fluids (89).
Changes in Components of the Circulating RAAS
in Normal Pregnancy
Angiotensinogen. As stated above, the activity of the circu-
lating renin-angiotensin system depends upon both the amount
of renin capable of interacting with AGT and the amount of
AGT. Plasma renin activity is a measure of the angiotensin-
forming capacity of plasma. AGT production parallels that of
estrogen; the correlation coefficient for AGT and estradiol-17
is 0.60 and for AGT and estriol, it is 0.68 (25). Thus, both AGT
(Fig. 2B) and ANG II levels rise progressively throughout
pregnancy (4). The significance of the increase in AGT in
human pregnancy (70) has been underestimated despite the
claim by Skinner in 1993 that “at all stages of pregnancy,
angiotensinogen is the most important factor determining plasma
renin activity and presumably ANG II production” (69).
Native AGT is a 62-kDa protein, although it can exist in
high-molecular-weight forms (see below). It is a serpin with
the cleavage site for renin (a Val-Leu bond) in a relatively
inaccessible site. Accessibility by renin to this site is improved
by a redox-induced conformational change. Oxidation of the
Cys 18⫺Cys 138 bond in AGT (89) significantly increases its
renin binding affinity in the presence of the (P)RR. Oxidized
AGT reacting with renin has a K
m
that is about 30% of reduced
AGT, while in the presence of the (P)RR, oxidized AGT has a
K
m
only 9% that of reduced AGT. That is, oxidized AGT has
Fig. 1. A: renin-angiotensin system. (P)RR, prorenin receptor; ACE, angioten-
sin-converting enzyme; ACE2, a homolog of angiotensin-converting enzyme;
APA, aminopeptidase A. AT
2
R and AT
1
R are ANG II receptors; AT
4
Ror
IRAP is a receptor for ANG IV and MasR a receptor for ANG (1–7).
B: angiotensin peptides. ANG (1–7) can be produced by ACE2 actions on
ANG II or ANG I.
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R92 CIRCULATING RENIN-ANGIOTENSIN SYSTEM IN PREGNANCY
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a higher affinity for renin than reduced AGT, and the presence
of the (P)RR further enhances AGT’s affinity for renin caused
by oxidation of AGT. (P)RR has no effect, however, on the K
m
of the reduced AGT-renin reaction [K
m
is 86% of that mea
-
sured in the absence of (P)RR]. Therefore, with increasing
levels of AGT in pregnancy, and the fact that the oxidized-to-
reduced ratio of AGT has been shown to be increased in
preeclampsia (89), the role of AGT has, as Skinner pointed out,
been underestimated, in terms of its ability to affect ANG II
production. Clearly, the roles of oxidized AGT and (P)RR in
the etiology of abnormal pregnancy outcomes, such as
preeclampsia, intrauterine growth restriction, and preterm
birth deserve detailed investigation. Other conformational
changes in the molecular structure of AGT may also alter
the kinetics of the renin-AGT reaction. For example, the
Met 235 polymorphism in the AGT gene is associated with
a conformational change that leads to an increased rate of
formation of ANG II (89).
The molecular weight of circulating AGT can vary because
it forms polymers. Monomeric AGT is a protein of 61.5 kDa or
65.5 kDa (depending on glycosylation) produced by the liver
(80). Polymeric forms of AGT alter the rate of the renin-AGT
reaction.
High-molecular-weight AGTs, which are different from
those in plasma from nonpregnant women, have been found
in plasma from pregnant women. Levels of high-molecular-
weight AGT rise throughout pregnancy and are about 16% of
total AGT; they increase further in pregnancy-induced hyper-
tension and hypertension that is exacerbated in pregnancy (79).
The reaction of high-molecular-weight AGT with renin is
slow (86).
High-molecular-weight AGTs were first described by Gor-
don and Sachin (20) and quantified by Tewksbury and Dart
(79). Five distinct forms exist in extra fetal tissues, i.e., am-
nion, chorion, and placenta, while only three forms exist in
plasma (78). In plasma from pregnant women, high-molecular-
weight AGTs are polymers complexed with other proteins, such
as the proform of eosinophil major basic protein (proMBP), which
is highly expressed in the placenta. Low levels of proMBP occur
in Down’s syndrome and are also associated with poor pregnancy
outcome (86). It is produced by the trophoblast placental X cells
(extravillous trophoblast) (54). 2:2 polymers of proMBP/AGT
and 2:2:2 of proMBP/AGT/Cd3g occur in plasma from pregnant
women (55). Cd3g is complement. ProMBP and Cd3g complexes
with AGT only occur in plasma from pregnant women, although
there are high-molecular-weight forms of AGT (140 and 100
kDa), which account for about 3–5% of total AGT in plasma from
nonpregnant subjects (46).
Therefore, not only are levels of plasma AGT increased in
pregnancy, but AGT also influences the rate of production of
ANG II, depending on its redox state and the amount com-
plexed with other proteins.
Prorenin and active renin. In the luteal phase of the men-
strual cycle, prorenin levels peak shortly after ovulation, while
active renin levels rise in the mid-luteal phase (68). This
suggests that ovarian prorenin is secreted at ovulation. The
ovarian follicle contains renin, 99% of which is in the form of
prorenin, although ANG I and ANG II are also both present,
suggesting that either prorenin is nonproteolytically activated
by binding to (P)RR or the very small amount of active renin,
perhaps formed spontaneously, is sufficient to generate ANG I
and ANG II (34).
Maternal plasma prorenin levels are at a maximum at 8–12
wk gestation (16, 70), being about 10 times nonpregnant levels
at their peak (16), while active renin levels do not rise until
⬃20 wk of pregnancy (Fig. 2A).
A strong correlation between serum renin levels (total) and
the number of ovarian follicles was found in women in whom
cycling was managed by LH, FSH, and human chorionic
gonadotrophin (hCG) (27). Ovarian prorenin is a major con-
tributor to circulating prorenin levels in early pregnancy.
Derkx et al. (16) demonstrated that in a woman with primary
ovarian failure in whom embryo transfer was performed,
plasma prorenin levels were only about 17% of those normally
BIRTH
100
1000
µU/mL
A
4-10
12-20
22-24
36-40
0
2
4
6
8
10
weeks gestation
Angiotensinogen (µg/mL)
*
**
B
Fig. 2. A: plasma prorenin () and active renin (Œ) levels throughout pregnancy
[redrawn with permisson from the Endocrine Society from the Journal of
Clinical Endocrinology, Derkx FH, Alberda AT, de Jonng FH, Zeilmaker FH,
Makovitz JW, and Schalekamp MA, vol. 65, 1987, permission conveyed
through Copyright Clearance Center; from Derkx et al. (16)]. B: angiotensino-
gen levels (g/ml) in maternal plasma throughout pregnancy. Levels were
measured by incubation of maternal plasma with an excess of human renal
renin. Angiotensinogen levels in early pregnancy were less than those mea-
sured after 20 wk gestation, *P ⬍ 0.035 and **P ⬍ 0.001 compared with
values obtained in first 10 wk gestation. [Drawn from raw data presented by
Skinner et al. (70)].
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seen in early pregnancy while levels of active renin, which are
secreted only by the kidney, were similar to those found in
normal pregnant women. The contribution of the uteroplacen-
tal unit to the maternal circulating prorenin levels has not been
demonstrated as convincingly.
Very high levels of prorenin might contribute to an increase
in active renin levels, perhaps after 20 wk gestation when the
materno-placental interface is fully established. This could
occur through spontaneous conversion to active renin, as it is
thought that there is an equilibrium between the two molecules
(67). Alternatively, prorenin could interact with the 28-kDa
soluble prorenin receptor, thus increasing the biological activ-
ity of the circulating RAAS through two actions, exposure of
the renin catalytic site, as well as affecting the rate of reaction
of renin with AGT.
It is surprising that despite the increased demand for reten-
tion of salt and water to compensate for the very significant
increase in cardiovascular volume that occurs in pregnancy (so
that it is effectively “underfilled”) and the salt-losing effects of
changes in renal function (discussed below), there is not a
marked increase in active renin until later in pregnancy. This
emphasizes the critical role of AGT in regulating plasma ANG
II levels early in gestation. This tightly controlled activity of
the RAAS through the action of estrogens on AGT provides a
“fail-safe” mechanism that offsets the natriuretic effects of the
high glomerular filtration rate (GFR) and high levels of pro-
gesterone, both of which are characteristic of normal preg-
nancy (1, 51). The “locking” of AGT synthesis to estrogen
production means that its regulation is freed from the control
by complex integratory pathways and/or maternal behavior,
e.g., salt intake.
Since active renin is only secreted by the kidney, one has to
conclude that the influence of AGT on plasma ANG II levels
results in a negative feedback suppression to midluteal levels
of active renin in early gestation, and only after 20 wk do those
mechanisms that normally balance renin activity to homeo-
static demand (i.e., renal sympathetic nerve activity, renal
perfusion pressure, and tubular flow dynamics) become signif-
icantly more influential in the control of maternal plasma renin
levels.
ACE. In normal pregnancy ACE activity does not change
throughout gestation (56). This may not be the case in patho-
logical pregnancies. Although we have not found any changes
in ACE levels at 15 wk gestation in women who go on to
develop preeclampsia or gestational hypertension (76), preg-
nant diabetic rats have higher serum ACE and lung ACE
than nondiabetic control animals; as well, ANG II levels are
higher (84).
ACE2. ACE2 has 40% homology with ACE. It removes a
single amino acid from either ANG II to form ANG (1–7) or
from ANG I to form ANG (1–9), which can subsequently be
cleaved to ANG (1–7) by ACE. ACE2 is primarily localized to
endothelial cells. It is upregulated in disease states such as
myocardial infarction and may be shed into plasma (31). ACE2
is expressed in high amounts in early gestational placentae on
the syncytiotrophoblast (59); levels of expression are lower at
term. In this location, placental ACE2 may cleave maternal
circulating ANG II to form ANG (1–7), a vasodilator peptide,
which acts via the Mas receptor (see below). As far as we can
tell, ACE2 has not been measured in human plasma from
pregnant women. This is because it is difficult to measure. Its
catalytic activity in human plasma is inhibited. The inhibitor is
a small-molecular-weight molecule; it is not a protein, nor is it
a divalent cation. Removal of the inhibitor by anion-exchange,
yielded plasma ACE2 activity of 4.44 ⫾ 0.56 pmol·ml
⫺1
·
min
⫺1
in plasma from nonpregnant women (31). Be that as it
may, the perfusion of maternal blood through the placenta and
exposure to ACE2 in syncytiotrophoblast may reflect an im-
portant physiological site of production of ANG (1–7).
ANG peptides. ANG I (the decapeptide) has no known
biological activity. ANG II, the octapeptide, is the most potent
of the ANG peptides (Fig. 1B) having 2 receptors, ANG II type
1 (AT
1
R) and type 2 receptors (AT
2
R). Additional ANG
peptides resulting from the removal of N-terminal amino acids
also exist in the circulation. Because biological activity de-
pends on the phenyalanine grouping at the carboxy end, the
heptapeptide, ANG III (des-aspartyl
1
-ANG II) is almost as
potent as ANG II. As well, ANG III appears to be the preferred
agonist for the AT
2
R in certain organs (e.g., the kidney), where
its actions via the tubular AT
2
R, release cGMP and cause a
profound natriuresis (30). The hexapeptide, ANG 3– 8, (also
known as ANG IV) and pentapeptide, ANG 4 – 8, have a
similar efficacy but are weak agonists of the AT
1
R because of
their poor affinity (15). ANG IV, however, does have a specific
receptor, IRAP, identified by Albiston et al. (3) that is involved
in cognition and memory. ANG (1–7), formed by the action of
a carboxypeptidase, such as ACE2 acting on ANG II (Fig. 1A)
or from ANG I via other pathways acts on a very different
receptor, the MasR (64).
Of these peptides, ANG II and ANG (1–7) have been most
studied in human pregnancy. At 15 wk gestation, ANG II
levels are lower and the ANG (1–7)/ANG II ratio higher in
women carrying male fetuses than in women carrying female
fetuses (75). Baker et al. (4) found that plasma ANG II levels
were elevated by the second trimester. By late gestation, ANG
I levels were 176.4 ⫾ 57.1 fmol/ml compared with nonpreg-
nant levels of 32.4 ⫾ 5.6 fmol/ml, and ANG II levels were
about 50% above nonpregnant levels while ANG (1–7) levels
were increased by about 34% [Fig. 3 (5)]. As explained above,
these high levels of ANG II and ANG (1–7) are predominantly
due, at least in early gestation, to the rising levels of AGT.
Since ACE2 activity has not been clearly determined in normal
human plasma, it is possible that the rise in ANG (1–7)
represents conversion from ANG II by ACE2 at the placental
ANG II
ANG (1-7)
Fig. 3. ANG II and ANG (1–7) levels in plasma from nonpregnant (NP) and
pregnant women in the third trimester. Data are reported as means ⫾ SE
values. [Redrawn from Brosnihan et al. (5)].
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interface (82, 83), but it is also possible that increased conver-
sion of ANG II to ANG (1–7) occurs in the pregnant kidney. In
Sprague-Dawley rats, Joyner et al. (28) showed that renal
levels of both ACE2 and ANG 1–7 were increased in the
middle to late stages of pregnancy. Coupled with the higher
renal blood flow of pregnancy, it is probable that renal ACE2
makes a significant contribution to circulating levels of ANG
(1–7) in human pregnancy (28).
Angiotensin Receptors
The roles of the circulating RAAS in human pregnancy
cannot be considered in isolation from changes in the density
of ANG receptors located in all those sites at which ANG
peptides have biological actions. The ANG II receptors (AT
1
R,
AT
2
R) are G protein-coupled receptors (15).
AT
1
R. ANG II/AT
1
R interactions acting via phospholipase C
increase cytosolic calcium, inhibit adenyl cyclase, and activate
tyrosine kinases, causing vasoconstriction, aldosterone synthe-
sis and secretion, and cardiac hypertrophy. Significantly, ANG
II acts within the central nervous system to stimulate thirst
(39), vasopressin secretion (38), and sympathetic nerve activity
(60), as well as inhibit cardiac vagal efferent nerve traffic (36).
These actions potentiate its peripheral vasoconstrictor actions
on vascular smooth muscle, thus leading to increased arterial
pressure. Through actions in the zona glomerulosa of the
adrenal cortex, ANG II/AT
1
R stimulates aldosterone synthesis
and secretion (72). Within the kidney, ANG II/AT
1
R interac
-
tions stimulate tubular sodium reabsorption (13). As well,
ANG II acting via AT
1
R partially mimics the actions of growth
factors using Ras pathways to activate MAPK; this action is
enhanced by ANG II transactivation of growth factor signaling.
Transactivation of EGF by ANG II stimulates MAPK and
calcium-dependent phosphorylation leading to activation of
growth factor proto-oncogenes (15).
AT
1
R density in vascular smooth muscle taken from preg
-
nant rats is suppressed by 1 M of estradiol (15). The changes
in AT
1
R density in the maternal vasculature in pregnancy are
unknown, but ANG II binding to platelet AT
1
Rs from pregnant
women has been described. Baker et al. (4) found that platelet
ANG II receptors were low throughout pregnancy, rising at 6
wk postpartum. Pawlak and MacDonald (57) showed that in
nonpregnant subjects there was a negative relationship between
ANG II levels and ANG II receptors. In early pregnancy this
relationship was lost because at this time, there was a “signif-
icant reduction or nil receptor capacity but only a slight
elevation in mean plasma angiotensin II concentration” and
“this phenomenon of reduced or absent binding persisted into
the third trimester when plasma angiotensin II was significantly
elevated compared with all other groups” (57).
It is well known that vascular reactivity to ANG II is
decreased both in terms of a reduction in pressor responses to
ANG II (19) and a reduction in the reactivity of the maternal
peripheral vasculature (35). Whether this is due to the coun-
teracting effects of other vasodilator influences in pregnancy or
to a reduction in AT
1
R is unknown, but the fact that hand
vascular reactivity of pregnant women to another vasoconstric-
tor, namely noradrenaline, was not altered, but the response to
ANG II was reduced (35), suggests that there is a reduction in
AT
1
R vascular receptor density, as found by others in platelets
(4, 57).
AT
2
R. ANG II acting via the AT
2
R receptor causes vasodi
-
lation and apoptosis. In pregnancy, myometrial AT
2
R are
downregulated, but in the uterine arteries of pregnant sheep, a
different picture is seen. Vascular AT
2
R are upregulated by
estrogens (62).
In uterine arteries from pregnant sheep, there are AT
2
R, but
these are not present in uterine arteries from nonpregnant sheep
(7, 41). Because ANG II/AT
2
R interactions mediate vasodila
-
tion via nitric oxide (NO) and bradykinin, the presence of
AT
2
R in the uterine arteries could be important in offsetting the
vasoconstrictor action of ANG II, so maintaining a high utero-
placental blood flow. This proposition would seem to be
supported by the finding in sheep that uteroplacental flow did
not change during short-term intravenous infusions of ANG
II of ⬍60 ng·kg
⫺1
·min
⫺1
(46) or 4-h infusions of 20 –30
ng·kg
⫺1
·min
⫺1
(74). However, when 20 –30 ng·kg
⫺1
·min
⫺1
intravenous infusions of ANG II were continued for 16 –24 h,
uteroplacental flow did decrease, and the fetuses became hy-
poxemic (74). Infusions (30 ng·kg
⫺1
·min
⫺1
) of ANG II for 24
h cause uterine arteries from pregnant sheep (studied in vitro)
to contract more vigorously in response to ANG II. This is due,
in part, to downregulation of AT
2
R. Thus AT
2
R in the pregnant
uterine vasculature protects against the vasoconstrictor actions
of ANG II unless high circulating levels of ANG II are
sustained over many hours, resulting in their downregulation
(40). In addition, in female rats, low doses of ANG II cause a
fall in blood pressure (BP) not seen in male rats (63). In
genetically modified mice, AT
2
R-null mice develop high blood
pressure in the third trimester (77), and AT
2
R receptor antag
-
onism abolishes the midgestation decline in BP in AT
1a
⫺/⫺
and
C57BL/6J mice (73). Thus, AT
2
R plays a role in regulation of
maternal blood pressure and uteroplacental flow in animal
models, and it is likely that AT
2
Rs are upregulated in the
systemic, as well as the uteroplacental vasculature of the
pregnant human.
MasR. In 2003, Santos et al. (65) showed that ANG (1–7)
acted via a G protein orphan receptor, Mas. ANG (1–7) acting
via this pathway is also a vasodilator via endothelium-depen-
dent mechanisms, in particular, via NO. ANG (1–7) is also
antiaquaretic and promotes thirst (29, 37), important actions of
the RAAS regulation of fluid and electrolyte homeostasis in
pregnancy.
Insulin-regulated aminopeptidase. IRAP, also known as the
AT
4
receptor, is the receptor for ANG IV (3). It is the same as
placental oxytocinase (45). ANG IV bound to IRAP inhibits it
(2). Estrogen treatment of ovariectomized ewes results in
downregulation of IRAP in the outer myometrial layer (45).
Whether or not the inhibitory effect of ANG IV on IRAP plays
a role in parturition is unknown at this time.
Role(s) of the Circulating RAAS in Pregnancy
Underfilled hypotensive cardiovascular system of pregnancy.
The RAAS is activated in the 2nd half of the menstrual cycle,
following ovulation. At this time, mean arterial pressure falls
(from 81.7 ⫾ 0.2 during the follicular phase to 75.4 ⫾ 0.2
mmHg in the proliferative phase), and systemic vascular resis-
tance is decreased (declines from 1,224 ⫾ 82 to 959 ⫾ 59
dynes·s
⫺1
·cm
⫺5
, Fig. 4A).
These changes in cardiovascular
function could stimulate renin release via the renal barorecep-
tor or increased renal sympathetic nerve activity.
Review
R95CIRCULATING RENIN-ANGIOTENSIN SYSTEM IN PREGNANCY
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00034.2013 • www.ajpregu.org
![Fig. 4. Changes in mean arterial pressure (MAP, mmHg), cardiac output (CO, l/min), and systemic vascular resistance (SVR, torr; A); as well as glomerular filtration rate (GFR, ml/min) and renal plasma flow (RPF, ml/min) (B) in pregnancy. Measurements were made in nonpregnant women and throughout pregnancy up to 36 wk. [Redrawn from Chapman et al. (8) with correction to x-axes; Macmillan Publishers Ltd., Kidney International, 54, 2056–2063, 1998].](/figures/fig-4-changes-in-mean-arterial-pressure-map-mmhg-cardiac-224n09v7.webp)
![Fig. 5. Changes in plasma renin activity (PRA; ng·ml 1·h 1) (A) and plasma aldosterone levels (ALDO; ng/dl) (B) in human pregnancy. [Redrawn from Chapman et al. (8); Macmillan Publishers Ltd., Kidney International, 54, 2056–2063, 1998].](/figures/fig-5-changes-in-plasma-renin-activity-pra-ng-ml-1-h-1-a-and-kuswobzq.webp)
![Fig. 2. A: plasma prorenin ( ) and active renin (Œ) levels throughout pregnancy [redrawn with permisson from the Endocrine Society from the Journal of Clinical Endocrinology, Derkx FH, Alberda AT, de Jonng FH, Zeilmaker FH, Makovitz JW, and Schalekamp MA, vol. 65, 1987, permission conveyed through Copyright Clearance Center; from Derkx et al. (16)]. B: angiotensinogen levels ( g/ml) in maternal plasma throughout pregnancy. Levels were measured by incubation of maternal plasma with an excess of human renal renin. Angiotensinogen levels in early pregnancy were less than those measured after 20 wk gestation, *P 0.035 and **P 0.001 compared with values obtained in first 10 wk gestation. [Drawn from raw data presented by Skinner et al. (70)].](/figures/fig-2-a-plasma-prorenin-and-active-renin-oe-levels-13ef6jdp.webp)
![Fig. 8. Changes in plasma noradrenaline (N-AD, pg/ml) (A) and atrial natriuretic peptide (ANP, pg/ml) (B) in human pregnancy. [Redrawn from Chapman et al. (8); Macmillan Publishers Ltd., Kidney International, 54, 2056– 2063, 1998].](/figures/fig-8-changes-in-plasma-noradrenaline-n-ad-pg-ml-a-and-1dvpveh4.webp)