Extracellular vesicles from preeclampsia disrupt the blood-brain barrier via reduced claudin-5: potential role of vascular endothelial growth factor

Sandoval, H.; Ibanez, B.; Contreras, M.; Troncoso, F.; Castro, F. O.; Caamano, D.; Mendez, L.; Escudero-Guevara, E. A.; Mistry, H. D.; Kurlak, L. O.; Vatish, M.; Acurio, J.; Escudero, C.

doi:10.1101/2024.04.10.588960

bioRxiv · 10.1101/2024.04.10.588960

Extracellular vesicles from preeclampsia disrupt the blood-brain barrier via reduced claudin-5: potential role of vascular endothelial growth factor

Sandoval, H.·Ibanez, B.·Contreras, M.·Troncoso, F.·Castro, F. O.·Caamano, D.·Mendez, L.·Escudero-Guevara, E. A.·Mistry, H. D.·Kurlak, L. O.·Vatish, M.·Acurio, J.·Escudero, C.

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Abstract

BackgroundPhysiopathology of life-treating cerebrovascular complications in preeclampsia are yet unknown. We investigated whether disruption of the blood-brain barrier (BBB), generated using circulating small extracellular vesicles (sEVs) from women with preeclampsia or placentae cultured under hypoxic conditions, impairs the expression of tight junction proteins, such as claudin 5 (CLDN5), mediated by VEGF and activation of VEGF receptor 2 (KDR). MethodssEVs were isolated from plasma (normal pregnancy, sEVs-NP, n=9); preeclampsia, sEVs-PE, n=9) or placental explants from normotensive pregnancies, cultured in normoxia (sEVs-Nor, n=10) or hypoxia (sEVs-Hyp, n=10). The integrity of the BBB was evaluated using in vitro (human and mice brain endothelial cell lines) and in vivo (non-pregnant C57BL/6 mice (4 to 5 months old, (n=10) were injected with sEVs-Hyp), models. ResultssEVs-PE and sEVs-Hyp reduced CLND5 levels (p<0.05) in the endothelial cell membrane without affecting other tight junction proteins. These results were negated with sEVs-PE sonication. sEVs-Hyp injected into non-pregnant mice generated neurological deficits and BBB disruption, specifically in the posterior area of the brain, associated with reduction in CLND5 levels in the brain cortex. Furthermore, sEVs-PE and sEVs-sHyp had higher VEGF levels than sEVs-NP and sEVs-Nor, respectively. Human brain endothelial cells exposed to sEVs-PE or sEVs-sHyp exhibited a reduction in the activation of KDR. ConclusionsEVs from hypoxic placentae and plasma from women with preeclampsia disrupt the BBB, via reduction of CLDN5, a phenomenon that may involve VEGF contained within these vesicles. These findings will improve the elucidation of cerebrovascular alterations in women with preeclampsia.

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Sandoval, H., Ibanez, B., Contreras, M., Troncoso, F., Castro, F. O., Caamano, D., Mendez, L., Escudero-Guevara, E. A., Mistry, H. D., Kurlak, L. O., Vatish, M., Acurio, J., Escudero, C.. 2024-04-15. Extracellular vesicles from preeclampsia disrupt the blood-brain barrier via reduced claudin-5: potential role of vascular endothelial growth factor. https://doi.org/10.1101/2024.04.10.588960

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