Related Experiment Video
Updated: May 7, 2025
Author Spotlight: Modeling an Aspect of Preeclampsia in Female Mice Using Hypoxic Human Placenta-Derived Small Extracellular Vesicles
Published on: January 26, 2024
Circulating extracellular vesicles and neutrophil extracellular traps contribute to endothelial dysfunction in
Alex Ramos1,2, Lina Youssef3,4, Patricia Molina1
1Hemostasis and Erythropathology Laboratory, Hematopathology, Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Insights
Preeclampsia (PE) involves harmful extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) that damage endothelial cells. EVs promote oxidative stress, while NETs activate complement, contributing to PE pathogenesis.
Area of Science:
- Obstetrics and Gynecology
- Immunology
- Vascular Biology
Background:
- Preeclampsia (PE) is a pregnancy complication marked by hypertension and proteinuria.
- Placenta-derived extracellular vesicles (EVs) are implicated in maternal-fetal communication and may contribute to PE.
- Neutrophil extracellular traps (NETs) are involved in other complement-mediated diseases, but their role in PE is unstudied.
Purpose of the Study:
- To investigate the impact of PE-derived EVs and NETs on endothelial cells (ECs).
- To determine the specific mechanisms by which EVs and NETs affect EC function in the context of PE.
Main Methods:
- EVs were isolated from sera of women with PE and normotensive controls.
- NETs were generated by incubating neutrophils with PE or control sera.
- Microvascular ECs were exposed to PE sera, depleted PE sera, or depleted sera supplemented with EVs or NETs.
- Changes in EC markers (VCAM-1, ICAM-1, VE-cadherin, eNOS, VWF), reactive oxygen species (ROS), and complement deposits (C5b-9) were assessed.
Main Results:
- PE sera significantly increased VWF, VCAM-1, and ROS in ECs compared to control sera.
- Depletion of EVs from PE sera reduced these effects, while adding PE-EVs to control sera increased them.
- PE-NETs significantly increased VWF, VCAM-1, and C5b-9 deposition, while decreasing VE-cadherin expression in ECs.
Conclusions:
- Circulating EVs from PE patients induce a pro-oxidant and pro-inflammatory state in ECs.
- NETs from PE patients potentiate complement system activation and alter EC function.
- Both EVs and NETs contribute to endothelial dysfunction in preeclampsia.
Background:
Preeclampsia (PE) is a pregnancy complication characterized by hypertension, proteinuria, endothelial dysfunction, and complement dysregulation. Placenta-derived extracellular vesicles (EVs), necessary in maternal-fetal communication, might contribute to PE pathogenesis. Moreover, neutrophil extracellular traps (NETs) play a pathogenic role in other complement-mediated pathologies, and their contribution in PE remains unexplored.
Materials And Methods:
EVs were isolated from PE (peEVs) and normotensive pregnant women sera. NETs were obtained incubating donor-pre-activated neutrophils with PE or control sera. Microvascular (HMEC) endothelial cells (ECs) were incubated with PE or control sera with or without (depleted sera) EVs or NETs, to assess changes in VCAM-1, ICAM-1, VE-cadherin, eNOS, VWF, ROS, and C5b-9 deposits. Results were expressed as fold increase vs. control.
Results:
VWF, VCAM-1, and ROS expression was significantly higher in cells exposed to PE sera vs. control (12.3 ± 8.1, 3.6 ± 2.3, and 1.8 ± 0.2, respectively, p < 0.05), though significantly lower in cells exposed to depleted PE (dPE) sera (6.1 ± 2.7, 0.7 ± 0.6, and 1.2 ± 0.1, respectively, vs. control, p < 0.05). EC exposure to depleted control sera supplemented with peEVs (dC+peEVs) significantly increased VWF, VCAM-1, and ROS compared to non-supplemented sera (4.5 ± 0.3, 2.8 ± 2.0, and 1.4 ± 0.2, respectively, p < 0.05). ICAM-1, VE-cadherin, and C5b-9 did not differ among groups. ECs incubated with PE-NETs increased VWF and VCAM-1 and decreased VE-cadherin expression vs. control (4 ± 1.6, 5.9 ± 1.2, and 0.5 ± 0.1, respectively, p < 0.05), and notably increased C5b-9 deposit (7.5 ± 2.9, p < 0.05). ICAM-1 and ROS did not differ.
Conclusions:
Both circulating EVs and NETs from PE pregnant women exhibit a deleterious effect on ECs. Whereas EVs trigger a pro-oxidant and proinflammatory state, NETs potentiate the activation of the complement system, as already described in PE.
