Upregulation of Angiotensin Converting Enzyme 2 and Angiotensin II to Angiotensin 1-7 Ratio in COVID-19-Positive Pregnancies Is Correlated with Lower Birth Weight

Introduction: The impact of COVID-19 on pregnancy remains incompletely understood. The presence of the primary SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), in the placenta suggests a potential vulnerability of this organ. Beyond the risk of vertical transmission, ACE2 may be depleted during viral entry, disrupting its biological functions. During pregnancy, ACE2 plays a critical role in placentation and hemodynamic adaptations by regulating the Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS). Hypothesis: We hypothesize that SARS-CoV-2 interaction with ACE2 may disrupt placentation and impairs uteroplacental circulation, contributing to clinical complications such as preeclampsia and intrauterine growth restriction. Objectives: To compare the expression of angiotensin (Ang) II, Ang 1-7, and ACE2 in placentas from SARS-CoV-2-infected pregnant women and uninfected controls. METHODS: Women admitted for labor at the Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Recife, Brazil, were tested for COVID-19 using nasopharyngeal RT-PCR. From March 2020 to September 2021, we recruited 160 COVID-19-negative controls and 126 COVID-19-positive participants. Obstetric and clinical data, as well as formalin-fixed paraffin-embedded placental biopsies, were collected. Participants were further stratified by COVID-19 severity. Histopathological analysis focused on identifying signs of malperfusion and inflammation were conducted. A Tissue Microarray block was created to analyze Ang II, Ang 1-7, and ACE2 expression through immunohistochemistry. Results: COVID-19 severity was associated with adverse pregnancy outcomes, including low birth weight, preterm birth, APGAR scores below 7, and fetal death. Placentas were lighter, and the placental-to-fetal weight ratio was higher in affected pregnancies. Ang II expression showed a trend towards higher levels in the COVID-19-positive group (105.3 ± 2 vs. 101.5 ± 3, p = 0.06), while ACE2 expression (107.6 ± 12 vs. 75.9 ± 14, p = 0.04) and the Ang II to Ang 1-7 ratio (0.99 ± 0.1 vs. 0.93 ± 0.1, p = 0.03) were significantly elevated. ACE2 expression correlated with lower birth weight and APGAR scores, while both ACE2 and the Ang II to Ang 1-7 ratio were linked to an increased placental-to-fetal weight ratio, indicative of fetal growth restriction. Conclusion: Our findings demonstrate a dysregulation of RAS in COVID-19-affected placentas, characterized by an elevated Ang II to Ang 1-7 ratio and increased ACE2 expression. The higher Ang II to Ang 1-7 ratio reflects a shift towards the vasoconstrictive and pro-inflammatory axis of RAS. Upregulation of ACE2 may increase susceptibility to placental SARS-CoV-2 infection. Although vertical transmission is rare, viral replication can compromise placental function, contributing to the heightened prevalence of adverse maternal-fetal outcomes in COVID-19 pregnancies. Further studies will assess ACE, SARS-CoV-2, inflammatory markers, and vascular density to deepen our understanding. Supported by Sao Paulo Research Foundation (FAPESP) proc:. 2022/02452-5 and 2017/17027-0. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.