AHA科学声明：评估肾素-血管紧张素-醛固酮系统在母体和后代心血管健康产前规划中的作用的临床前证据

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Hypertension

Hypertension. 2023;80:00–00. DOI: 10.1161/HYP.0000000000000227 TBD 2023 e1

AHA SCIENTIFIC STATEMENT

Appraising the Preclinical Evidence of the Role

of the Renin-Angiotensin-Aldosterone System

in Antenatal Programming of Maternal and

Offspring Cardiovascular Health Across the Life

Course: Moving the Field Forward: A Scientiﬁc

Statement From the American Heart Association

Barbara T. Alexander, PhD, FAHA, Chair; Andrew M. South, MD, Vice Chair; Phyllis August, MD; Mariane Bertagnolli, PhD;

Erin P. Ferranti, PhD; Justin L. Grobe, PhD; Emily J. Jones, PhD, FAHA; Analia S. Loria, PhD; Basmah Safdar, MD;

Maria Luisa Soledad Sequeira-Lopez, MD; on behalf of the American Heart Association Council on the Kidney in Cardiovascular

Disease; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Radiology and Intervention; Council on Hyper-

tension; and Council on Lifestyle and Cardiometabolic Health

ABSTRACT: There is increasing interest in the long-term cardiovascular health of women with complicated pregnancies and

their affected offspring. Emerging antenatal risk factors such as preeclampsia appear to increase the risk of hypertension

and cardiovascular disease across the life course in both the offspring and women after pregnancy. However, the antenatal

programming mechanisms responsible are complex and incompletely understood, with roots in alterations in the development,

structure, and function of the kidney, heart, vasculature, and brain. The renin-angiotensin-aldosterone system is a major

regulator of maternal-fetal health through the placental interface, as well as kidney and cardiovascular tissue development

and function. Renin-angiotensin-aldosterone system dysregulation plays a critical role in the development of pregnancy

complications such as preeclampsia and programming of long-term adverse cardiovascular health in both the mother and

the offspring. An improved understanding of antenatal renin-angiotensin-aldosterone system programming is crucial to

identify at-risk individuals and to facilitate development of novel therapies to prevent and treat disease across the life

course. Given the inherent complexities of the renin-angiotensin-aldosterone system, it is imperative that preclinical and

translational research studies adhere to best practices to accurately and rigorously measure components of the renin-

angiotensin-aldosterone system. This comprehensive synthesis of preclinical and translational scientiﬁc evidence of the

mechanistic role of the renin-angiotensin-aldosterone system in antenatal programming of hypertension and cardiovascular

disease will help (1) to ensure that future research uses best research practices, (2) to identify pressing needs, and (3) to

guide future investigations to maximize potential outcomes. This will facilitate more rapid and efﬁcient translation to clinical

care and improve health outcomes.

Key Words: AHA Scientiﬁc Statements ◼ aldosterone ◼ angiotensin-converting enzyme 2 ◼ hypertension ◼ pre-eclampsia ◼ pregnancy

◼ renin-angiotensin system

The antenatal period, spanning conception to birth,

is critical for maternal and fetal health. Exposure

to adverse health conditions and environmental

stressors during this time period can have long-term

consequences on the mother and her offspring. Brieﬂy

stated, antenatal programming happens when expo-

sures occur from conception through birth that alter

structural, physiological, and metabolic fetal devel-

opment and maternal health to improve short-term

survival but at the expense of programmed adverse

Hypertension is available at www.ahajournals.org/journal/hyp

Downloaded from http://ahajournals.org by on March 23, 2023

CLINICAL STATEMENTS

AND GUIDELINES

e2 TBD 2023 Hypertension. 2023;80:00–00. DOI: 10.1161/HYP.0000000000000227

Alexander et al Antenatal Programming of Cardiovascular Health

cardiovascular health in the long term (ie, developmen-

tal plasticity).1 For example, maternal hypertension, the

most common medical comorbidity in pregnancy, is a

major health concern and is associated with increased

risks of short-term mortality and morbidity, as well as

programmed chronic disease later in life in both the

mother and the fetus.2 Offspring of women with pre-

eclampsia have lower birth weight and higher blood

pressure throughout childhood and young adulthood

compared with unexposed offspring.3 Numerous pre-

clinical models have conﬁrmed this association,4 yet

the exact mechanisms remain incompletely understood.

Several of the major components of the renin-angio-

tensin-aldosterone system (RAAS) regulate several

key physiological processes in both mother and fetus

during pregnancy and the development and function

of the kidney and cardiovascular system. Most nota-

bly, these include the angiotensin-converting enzyme

(ACE)/angiotensin II (Ang II)/Ang II type 1 receptor

(AT1R) and the ACE2/angiotensin-(1–7) (Ang-[1–7])/

Mas receptor pathways. Dysregulation of the circulat-

ing and tissue-speciﬁc RAAS contributes to the patho-

genesis of numerous antenatal conditions, including

hypertensive disorders in pregnancy.5 RAAS dysregu-

lation is one potential mechanism for the long-term

programming of hypertension in offspring exposed to

preeclampsia and other adverse antenatal factors.4,6

Greater risk of long-term hypertension and cardio-

vascular disease is also observed in women after pre-

eclampsia, highlighting that the burden of programmed

cardiovascular disease is not limited to the offspring.7 It

is important to note that, despite decades of research,

recommendations for preeclampsia treatment have not

changed,8 and the prevalence of hypertension in preg-

nancy continues to increase.9 Treatment strategies vary

considerably around the world, with signiﬁcant dispari-

ties in the screening and follow-up for the development

of hypertension and cardiovascular disease in affected

women during the postpartum period and beyond, includ-

ing in women from disenfranchised populations in the

United States.10 In addition, emerging evidence indicates

that pregnancy may place women at greater risk for

severe acute respiratory syndrome coronavirus 2 (SARS-

CoV-2) infection, which in turn may increase the risk of

several pregnancy complications, including preeclampsia

and low birth weight, possibly related to altered ACE2

expression, the binding site for SARS-CoV-2.11,12 Thus,

the short- and long-term increased risk of hypertension

and cardiovascular disease in the mother and offspring

attributable to pregnancy complications remains a critical

health concern.

Despite decades of high-quality studies that have

provided insights into the mechanisms responsible for

the programming of cardiovascular disease associated

with complicated pregnancies, there remains a crucial

need in the ﬁeld to further characterize dysregulatory

events affecting the RAAS during this critical period

of life. Primary reasons for persistent knowledge gaps

include heterogeneity in the methods used in many pre-

clinical models and the complex nature of the RAAS that

makes accurate and reliable quantiﬁcation challenging.

Thus, the goal of this scientiﬁc statement is to summa-

rize the current state of knowledge related to preclini-

cal evidence of antenatal programming mechanisms of

long-term maternal and offspring cardiovascular health

as it relates to the role of several of the major RAAS

pathways using well-characterized preclinical models

of developmental programming. This scientiﬁc state-

ment identiﬁes gaps in knowledge that require further

research. Moreover, this scientiﬁc statement empha-

sizes the importance of better understanding program-

ming mechanisms for both investigators and clinicians

to develop targeted interventions to prevent or mitigate

the increased risk of hypertension and cardiovascular

disease. This is the ﬁrst step in an approach to reduce

future cardiovascular risk in women with complicated

pregnancies and their children.

A comprehensive literature search was conducted

from approximately September 15, 2021, to Novem-

ber 15, 2021, that encompassed preclinical and clini-

cal studies and reviews that were published in PubMed,

Scopus, and other relevant databases using standardized

methods. Key search words included but were not lim-

ited to pregnancy, preeclampsia, RAAS, high blood pres-

sure, hypertension, cardiovascular, renal, brain, placental

insufﬁciency, hypoxia, glucocorticoids, maternal under-

nutrition, offspring, and chronic health. The selection of

writing group members was based on a wide range of

expertise, including clinical and preclinical researchers

representing different backgrounds, geographic regions,

sexes, races, and ethnicities.

MATERNAL-PLACENTAL-FETAL INTERFACE

AND THE RAAS

Maternal Cardiovascular Physiology During

Pregnancy

Maternal cardiovascular and renal adaptations to preg-

nancy are essential to accommodate the physiologi-

cal stress imparted by the growing fetus and placenta.

Marked systemic vasodilation with decreased systemic

vascular resistance and subsequent lower blood pres-

sure characterizes early pregnancy starting at 4 to 6

weeks of gestation. This likely stimulates the mater-

nal circulating RAAS by the end of the ﬁrst trimester

to retain sodium and ﬂuid to increase plasma volume

progressively throughout gestation, up to 40% to 50%

higher than the prepregnancy baseline.13 Cardiac output,

renal blood ﬂow, and glomerular ﬁltration rate increase to

≈50% over baseline; these changes are apparent by the

second trimester and persist until term.

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CLINICAL STATEMENTS

AND GUIDELINES

Hypertension. 2023;80:00–00. DOI: 10.1161/HYP.0000000000000227 TBD 2023 e3

Alexander et al Antenatal Programming of Cardiovascular Health

The RAAS in Normal Pregnancy Physiology

The RAAS, a crucial regulator of blood pressure and

ﬂuid-electrolyte balance, particularly in pregnant women

and the fetus, is a key contributor to cardiovascular and

kidney development (Figure 1A). Assessment of RAAS

components in the maternal circulation during pregnancy

suggests that overall activation that contributes to the

aforementioned physiological cardiovascular changes.

In normotensive, healthy pregnant women, blood pres-

sure remains lower while plasma renin activity (PRA) and

aldosterone remain elevated until late in pregnancy when

blood pressure increases.14 Increased angiotensinogen

production and PRA lead to increased angiotensin I

concentrations, favoring augmented Ang II production

that occurs despite reduced serum ACE activity, in part

as a result of activation of additional RAAS pathways.15

Ang II–mediated increased aldosterone concentrations

directly stimulate renal sodium and ﬂuid retention to

increase blood volume.

Circulating and local tissue Ang II exerts key physi-

ological functions in many crucial steps of placentation,

including trophoblast invasion and migration, as well as

spiral artery remodeling.16 RAAS components show a

dynamic distribution throughout pregnancy. The AT1R is

expressed in trophoblasts in early pregnancy but also

in villous endothelial cells at term.17 Prorenin, (pro)renin

receptor, AT1R, and Ang II type 2 receptor proteins are

also expressed throughout gestation in trophoblasts

at the maternal-fetal interface and in invasive tropho-

blasts, whereas ACE is concentrated predominantly in

the fetal circulation, particularly in endothelial cells.18

The incremental ACE protein expression in fetal endo-

thelial cells throughout pregnancy favors enhanced Ang

II production in placental vessels from the fetal side,

where angiogenesis, an essential process for maintain-

ing fetal perfusion, continuously occurs.18 However, the

expected increased Ang II production in the fetus and

mother must be ﬁnely modulated to prevent excessive

vasoconstriction and cardiovascular remodeling that

could occur if Ang II concentrations increase above the

expected physiological range.19

Pregnancy also stimulates the ACE2/Ang-(1–7)

pathway to balance increased ACE/Ang II pathway

activity and to contribute to maternal hemodynamic

adaptations and placentation, trophoblast invasion,

decidualization, and vascular remodeling.15,20 ACE2

breaks down Ang II, and Ang-(1–7), acting on its Mas

receptor, antagonizes Ang II signaling through AT1R

modulation.6 Estrogens regulate the progressive RAAS

activation observed throughout gestation in part by

directly stimulating angiotensinogen production and

increasing ACE2 expression and activity in local tis-

sue.21 In rats, renal ACE2 and Ang-(1–7) are progres-

sively upregulated throughout pregnancy.22 ACE2 and

Ang-(1–7) are also expressed in trophoblasts, villous

vessel endothelial cells, primary villi vascular smooth

muscle cells, and the syncytium and decidua.23 ACE2/

Ang-(1–7) expression and activity in the placenta are

dynamic, with greater concentrations in the decidua in

early pregnancy that progressively change toward the

placental villous endothelial cells and trophoblasts in

late gestation.23 The presence of the ACE2/Ang-(1–7)

pathway in invasive trophoblasts surrounding the spi-

ral arteries, as well as in endothelial cells and vascular

smooth muscle cells, suggests that the ACE2/Ang-

(1–7) pathway helps regulate uterine artery tone and

reduce maternal systemic vascular resistance.15 There-

fore, ACE2-mediated conversion of Ang II into Ang-(1–

7) and intracellular signaling between AT1R and Mas

receptor are likely key factors regulating Ang II physi-

ological effects during pregnancy.

Additional RAAS pathways contribute to the Ang II–

Ang-(1–7) balance during pregnancy but are less well

characterized; thus, their role in antenatal programming

presents another important knowledge gap. The (pro)

renin receptor is crucial for many developmental and

physiological processes during pregnancy through sev-

eral signaling pathways, including Wnt/b-catenin and

mitogen-activated protein kinase.24 Neprilysin, another

metallopeptidase that converts angiotensin I to Ang-(1–

7), has unclear effects during pregnancy. Compared with

pregnant women with healthy weight, pregnant women

with overweight or obesity (body mass index ≥25 or ≥30

kg/m2, respectively) have lower endothelial cell neprilysin

expression in the fetus and placenta, and fetal weight

is associated inversely with circulating neprilysin levels

in cord blood.25 Uterine mast cell and natural killer cell

secretion of chymase, a serine protease that generates

Ang II independently of ACE, may contribute to decidual

vessel remodeling and subsequent fetal growth.26

The RAAS in Pregnancy Pathologies

Placental insufﬁciency is a hallmark of many adverse

pregnancy events that program later disease in the

offspring. Short- or long-term interruptions in the sufﬁ-

cient delivery of blood, oxygen, or nutrients to the fetus

can alter fetal growth and organ development, leading

to abnormal tissue structure and function, especially in

the kidneys. Adequate fetal perfusion requires sufﬁcient

maternal cardiovascular and placental health; hence,

interruptions in the maternal, placental, or fetal RAAS

can potentially adversely affect fetal and maternal car-

diovascular health in the short and long term (Figure 1B).

Human intrauterine growth restriction, a proxy for pla-

cental insufﬁciency, is associated with higher cord blood

Ang II concentration but no difference in fetal-placental

AT1R concentration compared with term pregnancies

with delivery by elective cesarean section.27 Uterine ves-

sel ligation or clamping during mid or late pregnancy

as a model of placental insufﬁciency and maternal

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CLINICAL STATEMENTS

AND GUIDELINES

e4 TBD 2023 Hypertension. 2023;80:00–00. DOI: 10.1161/HYP.0000000000000227

Alexander et al Antenatal Programming of Cardiovascular Health

preeclampsia commonly induces reduced glomerular

number and hypertension in the offspring. Uteroplacental

insufﬁciency in the rat model of reduced uterine perfu-

sion pressure at gestational day 14 is associated with

attenuated intrarenal RAAS activity in neonatal rats.28

The apparent bidirectional relationship between pre-

eclampsia and placental insufﬁciency remains a paradox

in the ﬁeld that can hinder accurate inferences about

RAAS measurements observed in preclinical models

and clinical studies. Placental insufﬁciency in preclinical

models and in women may be a precursor to maternal

hypertensive disorders. Preeclampsia, in turn, exacer-

bates placental insufﬁciency and may program adverse

cardiovascular health in affected women and their off-

spring independently of placental insufﬁciency. Although

the cause of preeclampsia is still unclear, intriguing pre-

clinical and clinical evidence suggests that several poten-

tially interrelated pathways are involved. Early-pregnancy

placental ischemia is associated with release of soluble

fms-like tyrosine kinase 1, a circulating soluble isoform of

Figure 1. Physiological roles of the RAAS in healthy and pathological pregnancies.

A, Expression and actions of the major RAAS components during healthy pregnancy. B, Expression and actions of the major RAAS

components during pathological pregnancies, including preeclampsia and placental insufﬁciency. Ang indicates angiotensin; ACE, angiotensin-

converting enzyme; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; AT1R-AA, angiotensin II type 1 receptor autoantibody;

BP, blood pressure; HTN, hypertension; PlGF, placental growth factor; PRA, plasma renin activity; RAAS, renin-angiotensin-aldosterone

system; sFlt-1, soluble fms-like tyrosine kinase 1; and VEGF, vascular endothelial growth factor.

Downloaded from http://ahajournals.org by on March 23, 2023

CLINICAL STATEMENTS

AND GUIDELINES

Hypertension. 2023;80:00–00. DOI: 10.1161/HYP.0000000000000227 TBD 2023 e5

Alexander et al Antenatal Programming of Cardiovascular Health

the vascular endothelial growth factor receptor that has

antiangiogenic properties. It binds free vascular endothe-

lial growth factor and placental growth factor, leading to

an imbalance of antiangiogenic and proangiogenic fac-

tors, resulting in maternal endothelial dysfunction, hyper-

tension, proteinuria, and glomerular endotheliosis.29

Increased levels of circulating AT1R autoantibodies

in women with preeclampsia, ﬁrst described in 1999,30

have been studied extensively both in preclinical models

of placental hypoperfusion or preeclampsia and in clini-

cal studies. These antibodies are directed to a speciﬁc

epitope on the second extracellular loop of the AT1R and

bind to human trophoblasts. Multiple studies suggest that

the antibodies may play an important role in the patho-

physiology of preeclampsia by inducing vasoconstriction,

hypertension, and increased coagulation.31 Antibodies

derived from women with preeclampsia induce placen-

tal soluble fms-like tyrosine kinase 1 production through

AT1R activation in pregnant mice, human placental villous

explants, and human trophoblast cells.32 Human studies

have shown that these antibodies can be detected early

in pregnancy in women who later develop preeclampsia

and that, once preeclampsia develops, >95% of women

have the antibodies, which also correlate with disease

severity.33 However, signiﬁcant limitations remain in mea-

suring these autoantibodies accurately, and their clinical

signiﬁcance remains unclear.34

RAAS contributions to preeclampsia development

and progression remain elusive as well, with conﬂict-

ing ﬁndings and much debate resulting mainly from a

lack of consensus of methodological rigor.35 It remains

unknown whether RAAS dysregulation is a prerequisite

for preeclampsia development or a consequence. Acti-

vation of tissue RAAS and, by extension, the circulating

RAAS is necessary to meet and regulate the growing

demands of the fetus to ensure a healthy pregnancy.

Although there is consensus that placental alterations

are a principal causal mechanism in preeclampsia, it

remains unclear what role the RAAS has and whether

the observed changes in the circulating RAAS in women

with preeclampsia (eg, lower PRA) contribute to the dys-

regulation of maternal kidney and vascular function or

are altered in response to changes induced by angio-

genic factor dysregulation. Leading theories suggest

that abnormal or shallow placentation with defective spi-

ral arteriolar remodeling, reduced placental blood ﬂow,

and increased placental oxidative stress contributes to

preeclampsia pathogenesis.35 This abnormal placental

development may contribute to underexpression or over-

expression of placental RAAS components and excess

shedding of placental particles such as miRNA that tar-

get RAAS mRNA.36

Subsequent release of RAAS components into the

maternal circulation from the fetal-placental unit (eg,

increased Ang II, decreased Ang-[1–7]) may alter

the systemic and tissue-speciﬁc maternal RAAS,

including the intrarenal RAAS, subsequently reduce

uteroplacental blood ﬂow, and further drive placental

damage.35,37 Women who develop preeclampsia dem-

onstrate decreased glomerular ﬁltration rate, PRA,

and aldosterone before and at the time of diagnosis,

consistent with a volume-expanded circulation.38 Pla-

cental and plasma soluble (pro)renin receptor levels

are higher in women with preeclampsia compared with

women with normal pregnancies.39 During preeclamp-

sia, neprilysin levels are higher in the placenta and in

circulating extracellular vesicles derived from syncytio-

trophoblasts.40 Maternal vascular endothelial chymase

expression is increased in preeclampsia.41 In addi-

tion, these RAAS components may lead to secondary

changes in neurohormonal regulation of cardiovascular

and kidney function that program hypertension and

cardiovascular disease.42 However, the precise timing

of these RAAS changes and their importance to later

programmed disease remain unknown.

OVERVIEW OF MAJOR PRECLINICAL

PROGRAMMING MODELS

Numerous preclinical models using different pro-

gramming events in various animal species have

demonstrated consistently that programmed RAAS

alterations in the antenatal period can lead to hyper-

tension development in women and their offspring

(Figure 2). Among the most widely studied are mod-

els of placental insufﬁciency and maternal protein or

global nutrition restriction or excess in rodents and

sheep (Table 1). Within these models, speciﬁc ante-

natal events include maternal-fetal vascular supply

disruptions, maternal stress, and exogenous expo-

sures such as glucocorticoids. Although most models

attempt to induce fetal growth restriction, it is well

documented that programming mechanisms can occur

independently of placental insufﬁciency or growth

restriction. Because human nephrogenesis is com-

plete by 36 weeks’ gestation, most preclinical models

target equivalent windows in animals in which nephro-

genesis continues after birth (eg, the ﬁrst 10–12 days

of postnatal life in rodents) to investigate the effects

of exposures during organogenesis on long-term kid-

ney function and cardiovascular health.

However, the programming effects of antenatal

exposures on the RAAS are heterogeneous, depending

on the animal model (species, strain), exposure (tim-

ing, severity, duration), and tissue of interest. Choice of

model, exposure, and timing often depends on whether

the investigator is interested in a speciﬁc tissue (kid-

ney, heart, brain, or vasculature) and sex- or age-spe-

ciﬁc effects on RAAS programming.43 Variability in the

timing of programmed events has led to heterogeneity

among reported results and contributed to paradoxes

in the ﬁeld. Early, mid, late, or pan-gestation exposures

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