Increased Placental Anti-Oxidant Response in Asymptomatic and Symptomatic COVID-19 Third-Trimester Pregnancies

Abstract

Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (OxS) being well documented in different organs, the molecular pathways underlying placental OxS in late-pregnancy women with SARS-CoV-2 infection are poorly understood. Herein, we performed an observational study to determine whether placentae of women testing positive for SARS-CoV-2 during the third trimester of pregnancy showed redox-related alterations involving Catalase (CAT) and Superoxide Dismutase (SOD) antioxidant enzymes as well as placenta morphological anomalies relative to a cohort of healthy pregnant women. Next, we evaluated if placental redox-related alterations and mitochondria pathological changes were correlated with the presence of maternal symptoms. We observed ultrastructural alterations of placental mitochondria accompanied by increased levels of oxidative stress markers Thiobarbituric Acid Reactive Substances (TBARS) and Hypoxia Inducible Factor-1 α (HIF-1α) in SARS-CoV-2 women during the third trimester of pregnancy. Importantly, we found an increase in placental CAT and SOD antioxidant enzymes accompanied by physiological neonatal outcomes. Our findings strongly suggest a placenta-mediated OxS inhibition in response to SARS-CoV-2 infection, thus contrasting the cytotoxic profile caused by Coronavirus Disease 2019 (COVID-19).

Keywords: COVID-19; mitochondria; oxidative stress; placenta; pregnancy.

Figure 1

Effects of SARS-CoV-2 infection on placenta ultrastructure. (A,B) Representative images of a placenta from a control woman (A) and a SARS-CoV-2-infected woman (B) showing cells of syncytiotrophoblast (stc) and cytotrophoblast (ctc); arrows indicate the basal membrane (bm) that separates the trophoblast layer from the villous stroma (vs). Note the large amount of vacuolar structures infiltrating the cytoplasm of trophoblast cells. (C) Higher magnification showing mitochondria (mito) in a syncytiotrophoblast cell from a control placenta. Note the normal aspect of cristae. (D) Mitochondria in a trophoblast cell from a placenta of a woman with COVID-19. Note the presence of enlargements with noticeable reduction in cristae. The remaining cristae appear somewhat expanded. (E,F) Severely altered mitochondria in the placentae of women with COVID-19. Note the electro-lucent matrix, the strong reduction in cristae, and the presence of abnormal membranous inclusions. er: endoplasmic reticulum.

Figure 2

Effects of SARS-CoV-2 infection on oxidative stress markers in the placenta from the a-COVID-19, s-COVID-19, and CTRL groups. (A) TBARS and (B) HIF-1α expression in the placenta from the CTRL, a-COVID-19, and s-COVID-19 groups. Statistical significance was set at p < 0.05. * p < 0.05 versus CTRL. The Kruskal–Wallis test and Mann–Whitney U-test with a Bonferroni correction were used.

Figure 3

Effects of SARS-CoV-2 infection on antioxidant defense markers in the placenta from the a-COVID-19, s-COVID-19, and CTRL groups. (A) mRNA expression and (C) enzymatic activities of CAT in the placentae from the CTRL, a-COVID-19, and s-COVID-19 groups; (B) mRNA expression and (D) enzymatic activity of SOD in the placentae from the CTRL, a-COVID-19, and s-COVID-19 groups. Statistical significance was set at p < 0.05. * p < 0.05 versus CTRL. The Kruskal–Wallis test and Mann–Whitney U-test with Bonferroni correction were used.

Figure 4

TBARS, HIF-1α, CAT, and SOD expression in the placentae of COVID-19-positive women with and without pregnancy-related comorbidities. (A) TBARS and (B) HIF-1α placental expression in CTRL, uncomplicated COVID-19, Placental malperfusion (P. Malperfusion) COVID-19, and Pathological CTG COVID-19 groups; (C) mRNA expression and (E) enzymatic activity of CAT in the placentae of the CTRL, uncomplicated COVID-19, Placental malperfusion COVID-19, and Pathological CTG COVID-19 groups; (D) mRNA expression and (F) enzymatic activity of SOD in the placentae of the CTRL, uncomplicated COVID-19, Placental malperfusion COVID-19, and Pathological CTG COVID-19 groups. Statistical significance was set at p < 0.05. * p < 0.05 versus CTRL. The Kruskal–Wallis test and Mann–Whitney U-test with a Bonferroni correction were used.