Acute Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Pregnancy Is Associated with Placental Angiotensin-Converting Enzyme 2 Shedding

Abstract

Although human placental tissues may be infected by SARS-CoV-2, the rate of fetal transmission is low, suggesting either viral neutralization or a barrier at the maternal-fetal interface. Angiotensin-converting enzyme (ACE)-2, the main receptor for SARS-CoV-2, is expressed as cell surface and soluble forms regulated by a metalloprotease cleavage enzyme, ADAM17. ACE2 is expressed in the human placenta, but the regulation of placental ACE2 expression in relation to timing of maternal SARS-CoV-2 infection in pregnancy is not well understood. In this study, we evaluated ACE2 expression, ADAM17 activity and serum ACE2 abundance in a cohort of matched villous placental and maternal serum samples from Control pregnancies (SARS-CoV-2 negative, n=8) and pregnancies affected by symptomatic maternal SARS-CoV-2 infections in the 2 nd trimester (“2 nd Tri COVID”, n=8) and 3rd trimester (“3 rd Tri COVID”, n=8). In 3 rd Tri COVID as compared to control and 2 nd Tri-COVID villous placental tissues ACE2 mRNA expression was remarkably elevated, however, ACE2 protein expression was significantly decreased with a parallel increase in ADAM17 activity. Soluble ACE2 was also significantly increased in the maternal serum from 3 rd Tri COVID infections as compared to control and 2 nd Tri-COVID pregnancies. These data suggest that in acute maternal SARS-CoV-2 infections, decreased placental ACE2 protein may be the result of ACE2 shedding. Overall, this work highlights the importance of ACE2 for ongoing studies on SARS-CoV-2 responses at the maternal-fetal interface.

Potential molecular and cellular mechanisms for adverse placental outcomes in pregnancies complicated by SARS-CoV-2 infection—A scoping review

“…Several papers reported differences in expression of genes and or levels of proteins involved in the angiotensin converting enzyme two (ACE2) pathway. In placentas from participants with SARS-CoV-2 infection during the third trimester, expression of ACE2, protein and mRNA, were reduced compared to controls [ 39 , 40 ]. In placenta from participants with infection during the second trimester this pattern was not observed [ 39 ].…”

“…In placentas from participants with SARS-CoV-2 infection during the third trimester, expression of ACE2, protein and mRNA, were reduced compared to controls [ 39 , 40 ]. In placenta from participants with infection during the second trimester this pattern was not observed [ 39 ]. ACE2 levels were also reported to be lower in asymptomatic/mild infections compared to severe infection [ 31 ].…”

“…ACE2 levels were also reported to be lower in asymptomatic/mild infections compared to severe infection [ 31 ]. Infection was reported to be associated with increased levels of a disintegrin and metalloprotease domain 17 (ADAM17) [ 39 ]. No differences were found in expression levels of transmembrane protease serine 2 (TMPRSS2) [ 31 ] in infected compared to SARS-CoV-2 negative controls.…”

“…ACE2 plays a counter-regulatory role by converting AngII to Ang1-7, which binds to the G-protein coupled receptor (GPCR) Mas to promote vasodilation [ 55 ]. Depletion of ACE2 levels due to sequestration by SARS-CoV-2 may lead to associated effects on the RAS system which in turn may be linked to placental pathology and associated adverse pregnancy outcomes [ 39 , 40 , 56 ].…”

What is the Hidden Biological Mechanism Underlying the Possible SARS-CoV-2 Vertical Transmission? A Mini Review

“…Analyzing different biological specimens and the presence of antibodies in the maternal blood, several studies pointed to the transplacental passage of SARS-CoV-2 viral particles through the maternal-fetal interface, with an estimated rate of vertical transmission ranging from 3 to 8% of cases ( Bwire et al, 2021 ; Kotlyar et al, 2021 ; Taglauer et al, 2022 ). Concerns over SARS-CoV-2 vertical transmission are appropriate, due to the tropism for the cells of the maternal-fetal interface ( Li N. et al, 2020 ).…”