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

Am J Physiol Regul Integr Comp Physiol. 2021 Dec 1;321(6):R833-R843. doi: 10.1152/ajpregu.00211.2021. Epub 2021 Oct 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Angiotensin-Converting Enzyme 2 / therapeutic use
  • Animals
  • Blood Pressure
  • COVID-19 / enzymology
  • COVID-19 / physiopathology
  • COVID-19 / virology
  • Female
  • Fetal Growth Retardation / enzymology
  • Fetal Growth Retardation / physiopathology
  • Humans
  • Inflammation Mediators / metabolism
  • Placenta / enzymology*
  • Placenta / physiopathology
  • Pre-Eclampsia / enzymology
  • Pre-Eclampsia / physiopathology
  • Pregnancy
  • Pregnancy Complications / drug therapy
  • Pregnancy Complications / enzymology*
  • Pregnancy Complications / physiopathology
  • Pregnancy Complications, Infectious / enzymology
  • Pregnancy Complications, Infectious / physiopathology
  • Pregnancy Complications, Infectious / virology
  • Renin-Angiotensin System*
  • SARS-CoV-2 / pathogenicity
  • Uterus / enzymology*
  • Uterus / physiopathology
  • Water-Electrolyte Balance


  • Inflammation Mediators
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2