SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system

Med. 2021 May 14;2(5):575-590.e5. doi: 10.1016/j.medj.2021.04.009. Epub 2021 Apr 13.


Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear.

Methods: We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S).

Findings: Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia.

Conclusions: SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women.

Funding: NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).

Keywords: ACE2; AT1-AA; AT1R; PlGF; decidua; extravillous trophoblasts; placenta; pre-eclampsia; pregnancy; sFlt1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • COVID-19*
  • Female
  • Humans
  • Placenta / metabolism
  • Placenta Growth Factor / metabolism
  • Pre-Eclampsia* / metabolism
  • Pregnancy
  • Pregnancy Complications, Infectious* / metabolism
  • Renin-Angiotensin System
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Placenta Growth Factor
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • Angiotensin-Converting Enzyme 2