ACE2: a key modulator of the renin-angiotensin system and pregnancy

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound protein containing 805 amino acids. ACE2 shows approximately 42% sequence similarity to somatic ACE but has different biochemical activities. The key role of ACE2 is to catalyze the vasoconstrictor peptide angiotensin (ANG) II to Ang-(1-7), thus regulating the two major counterbalancing pathways of the renin-angiotensin system (RAS). In this way, ACE2 plays a protective role in end-organ damage by protecting tissues from the proinflammatory actions of ANG II. The circulating RAS is activated in normal pregnancy and is essential for maintaining fluid and electrolyte homeostasis and blood pressure. Renin-angiotensin systems are also found in the conceptus. In this review, we summarize the current knowledge on the regulation and function of circulating and uteroplacental ACE2 in uncomplicated and complicated pregnancies, including those affected by preeclampsia and fetal growth restriction. Since ACE2 is the receptor for SARS-CoV-2, and COVID-19 in pregnancy is associated with more severe disease and increased risk of abnormal pregnancy outcomes, we also discuss the role of ACE2 in mediating some of these adverse consequences. We propose that dysregulation of ACE2 plays a critical role in the development of preeclampsia, fetal growth restriction, and COVID-19-associated pregnancy pathologies and suggest that human recombinant soluble ACE2 could be a novel therapeutic to treat and/or prevent these pregnancy complications.

Keywords: COVID-19; angiotensin-converting enzyme 2; fetal growth restriction; preeclampsia; pregnancy.

Figure 1.

Schematic representation of the renin-angiotensin system (RAS). ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; ANG, angiotensin; AT₁R, angiotensin II type 1 receptor, AT₂R; angiotensin II type 2 receptor; BP, blood pressure; MasR, Mas receptor; NEP, neprilysin.

Figure 2.

Angiotensin-driven oxidative stress and inflammation pathways. ANG II/AT₁R signaling enhances NF-κB-mediated translation of proinflammatory factors and, in turn, increases inflammatory cell recruitment. ANG II/AT₁R signaling enhances NAD(P)H oxidase activation to increase reactive oxygen species (ROS) and enhance markers of oxidative stress. Increased ROS levels further enhance NF-κB-mediated translation. The actions of ACE2 in degrading ANG II and producing Ang-(1–7) will result in activation of the Ang-(1–7)/MasR pathway. Ang-(1–7)/MasR signaling reduces inflammation by inhibiting NAD(P)H oxidase and/or NF-κB-mediated oxidative stress and inflammation. Furthermore, Ang-(1–7)/MasR signaling enhances Nrf-2-mediated antioxidant and cytoprotective gene translation. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ANG, angiotensin; AT₁R, angiotensin II type 1 receptor; eNOS, endothelial nitric oxide synthase; HO-1, hemoxygenase 1; IL, interleukin; MasR, Mas receptor; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor-κB; Nrf2, nuclear factor-erythroid-2-related factor; NQO1, NAD(P)H quinone dehydrogenase 1; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β.

Figure 3.

Angiotensin-converting enzyme 2 (ACE2) shedding. A: full-length ACE2 protein contains 805 amino acids and consists of a signal peptide (SP) at the NH₂ terminus, a large carboxypeptidase (catalytic) domain containing a zinc-binding motif “HEXXH,” and a collectrin domain containing a protease cleavage (PC) site, transmembrane (TM) domain, and a short 22 amino -acid cytoplasmic tail at the COOH terminus. The extracellular component of ACE2 can be cleaved and released into the extracellular space as soluble ACE2 (sACE2). A and B: The extracellular compartment of ACE2 can be cleaved by α-disintegrin and metalloprotease (ADAM) 17 between amino acids 716–741 (74) and/or 708–709 (75). Recent studies by Heurich et.al. (76) suggest that the arginine/lysine (Arg/Lys) residues located at amino acids 652–659 are essential for ACE2 shedding by ADAM 17 because they act as a signal to initiate ADAM 17 recognition of the downstream cleavage site. In addition, while disputed in the literature, Jia et.al.(74) have shown that ADAM 10 may also be involved in ACE2 ectodomain shedding. Type II transmembrane serine proteases TMPRSS2 and HAT cleave full-length ACE2 at amino acids 697–716; however, whether this cleavage results in a biologically stable form of sACE2 has not been confirmed (76).

Figure 4.

Overarching hypothesis. Angiotensin converting enzyme 2 (ACE2) protects against placental inflammation and oxidative stress. Downregulation of placental ACE2 (e.g., because of inhibition or SARS-CoV-2 spike protein binding) results in placental inflammation and oxidative stress, which limits fetal growth and causes the classical symptoms of preeclampsia (hypertension and proteinuria). Treatment with recombinant human (rh)sACE2 and/or activation of ACE2 may prevent SARS-CoV-2 binding to the placenta (in the case of (rh)sACE2) and protect against growth restriction and preeclampsia.