Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19

Abstract

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.

COVID-19 in pregnancy: placental pathological patterns and effect on perinatal outcome in five cases

“…According to the literature, these lesions are common in the placenta of COVID-19-positive women [7,[38][39][40][41][42][43][44][45][46][47][48][49] in the third trimester, and might be related to hypoxia. In cases of COVID-19 in pregnancy, hypoxia in the third trimester may be related to severe disease, particularly affecting the respiratory system [50], but may also be due to more common physiologically adaptive changes occurring in pregnancy, such as: -increased blood volume and oxygen consumption, increased uterine volum [51]; − systemic inflammatory or hypercoagulable state [7,40,52,53].…”

“…Although intervillous thrombi are generally incidental findings [54], they may be associated with maternal hypertensive disorder [55][56][57] or diabetes [58] and coexist with infarctions; they may also be responsible for intrauterine growth retardation [59]. These lesions are frequent in cases of COVID-19 and may be related to hypercoagulability in the intervillous space [40,53].…”

Novel Ratio Soluble Fms-like Tyrosine Kinase-1/Angiotensin-II (sFlt-1/ANG-II) in Pregnant Women Is Associated with Critical Illness in COVID-19

“…It is known that sFlt-1 causes endothelial dysfunction, sensitizing the endothelial cells to the effect of ANG-II in the whole endothelium and placenta [15]. In critically ill non-pregnant COVID-19 patients, there is an upregulation of sFlt-1, suggesting that this protein might play a role in the COVID-19-associated systemic endothelial dysfunction [16,17].…”

SARS-CoV-2 (COVID-19) en gestación y placenta: una revisión narrativa sobre el estado del arte

“…La evidencia del aumento de citocinas proinflamatorias placentarias en presencia del virus, junto con la detección de macrófagos y alteraciones de tipo inflamatorio en los vasos placentarios, permiten proponer que el SARS-CoV-2 podría inducir vasculopatía placentaria y alteraciones de la perfusión materno-fetal. Entre los estudios celulares y moleculares cabe destacar el trabajo de Flores-Pliego, et al 50 , en el que se describe que en las placentas de mujeres con COVID-19 hay un aumento de la expresión del factor von Willebrand (fvW) en las células endoteliales, junto con una disminución en la expresión endotelial de proteínas de adhesión celular VE-cadherina y claudina-5 en los casos de COVID-19 grave. El aumento del fvW se asociaría con un mayor riesgo de trombosis en los vasos placentarios, mientras que la disminución de las proteínas de adhesión se relacionaría con disfunción endotelial asociada al proceso inflamatorio placentario detectado en los casos graves de COVID-19 50 .…”