Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age

Abstract

Introduction: An imbalance in angiotensin (Ang) peptides could contribute to the pathophysiology of preeclampsia (PE) and poor fetal growth.

Methods: We measured maternal plasma levels of Ang peptides and converting enzymes in non-pregnant women (n = 10), in normal pregnant women (n = 59), women delivering small for gestational age babies (SGA, n = 25) across gestation (13-36 weeks) and in women with PE (n = 14) in their third trimester.

Results: Plasma ACE, ACE2, and Ang-(1-7) levels, and ACE2 activity were significantly higher in normal pregnant women compared with non-pregnant women; neprilysin (NEP) levels were not changed. In SGA pregnancies, ACE and ACE2 levels were higher in early-mid pregnancy compared with normal pregnant women. In women with PE, plasma ACE, ACE2, NEP, and Ang-(1-7) levels and ACE2 activity were lower than levels in normal pregnant women.

Conclusion: The higher plasma ACE2 levels and activity in pregnancy could be driving the higher Ang-(1-7) levels. The early gestation increases in ACE and ACE2 levels in SGA pregnancies highlights the possibility that these enzymes could be used as potential early biomarkers of poor fetal growth. In women with PE, the reduced ACE2 and NEP levels at term, could be contributing to the reduction in Ang-(1-7) levels. These findings suggest that dysfunctional relationships between two key enzymes in the circulating RAS are involved in the pathogenesis of PE and SGA. Since soluble ACE2 can prevent binding of the novel coronavirus, SARS-CoV-2, to membrane bound ACE2, the interplay between ACE2 and the coronavirus and its impact in pregnancy requires further investigation.

Keywords: angiotensin converting enzyme 2 (ACE2); angiotensin peptides; preeclampsia; pregnancy; small for gestational age.

FIGURE 1

Schematic representation of the RAS cascade. ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; NEP, neprilysin; AT₁R, Angiotensin II type 1 receptor, AT₂R; Angiotensin II type 2 receptor.

FIGURE 2

Correlations between (A) ACE2 levels and ACE2 activity (non-pregnant and all pregnancy groups combined), (B) ACE2 levels and Ang-(1-7) levels, and (C) ACE2 activity and Ang-(1-7) levels.

FIGURE 3

Plasma levels and activity of ACE, ACE2, and NEP in non-pregnant (NP) and pregnant women (A–D). Plasma levels of Ang-(1-7) were measured by radioimmunoassay in NP and pregnant women (E). Plasma ACE2/ACE ratio and ACE2 activity/ACE ratio in NP and pregnant women (F,G). Data are expressed as median and interquartile range. n = 9–10 samples for the NP group (black box), n = 7–35 samples/group for 13, 18, 30, and 36 weeks of normal pregnancy (white box). P-values were calculated using a Kruskal–Wallis test (with Dunn’s multiple comparison test). *P < 0.05, **P < 0.01, ***P < 0.001 versus NP.

FIGURE 4

Plasma levels and activity of (A) ACE, (B,C) ACE₂, and (D) NEP as well as levels of (E) Ang-(1-7), (F) ACE2/ACE ratio, and (G) ACE2 activity/ACE2 ratio in normal and SGA pregnancies. Data are expressed as median and interquartile range. n = 5–36 samples/group for normal pregnancies (gray box) and n = 4–15 samples/group for SGA pregnancies (white box). P-values were calculated using a two-way ANOVA (mixed effect model with Fisher’s LSD multiple comparison test). ^∗P < 0.05, ^∗∗P < 0.01, ^∗∗∗P < 0.001 versus normal pregnancy group of the same gestational age.

FIGURE 5

Plasma levels and activity of (A) ACE, (B,C) ACE2, and (D) NEP as well as (E) levels of Ang-(1-7), and (F) ACE2/ACE ratio in the third trimester (≥26 weeks of gestation) in women with normal pregnancies (gray box) and women with preeclampsia (PE; white box). Data are expressed as median and interquartile range. n = 16–32 for normal pregnancy group and n = 8–14 samples for the PE group. *P < 0.05, **P < 0.01, ***P < 0.001 versus normal pregnancy group.