Extracellular Vesicles From Preeclampsia Disrupt the Blood-Brain Barrier by Reducing CLDN5.

Area of Science:

• Obstetrics and Gynecology
• Neuroscience
• Vascular Biology

Background:

• The underlying causes of severe cerebrovascular issues in preeclampsia remain unclear.
• Preeclampsia is associated with significant risks of stroke and other neurological complications.

Purpose of the Study:

• To investigate if small extracellular vesicles (sEVs) from preeclampsia patients or placentas under hypoxia disrupt the blood-brain barrier (BBB).
• To determine the role of tight junction proteins, vascular endothelial growth factor (VEGF), and KDR (VEGFR2) in sEV-mediated BBB disruption.

Main Methods:

• Utilized sEVs from normal pregnancy, preeclampsia, and placentas cultured in normoxia or hypoxia.
• Assessed BBB integrity using in vitro brain endothelial cell models and in vivo mouse models injected with sEVs.

Main Results:

• sEVs from preeclampsia (sEVs-PE) and hypoxic placentas (sEVs-Hyp) reduced claudin-5 (CLDN5) levels.
• In vivo, sEVs-Hyp induced neurological deficits and BBB disruption, linked to CLDN5 reduction.
• sEVs-PE and sEVs-Hyp showed elevated VEGF; sEVs-PE reduced KDR activation.

Conclusions:

• sEVs-PE disrupt the BBB, an effect mimicked by sEVs-Hyp, involving reduced CLDN5 and elevated VEGF.
• KDR activation does not appear to mediate the CLDN5 downregulation observed with sEVs-Hyp.
• Findings enhance understanding of cerebrovascular pathophysiology in preeclampsia.