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Plasmodium falciparum impairs Ang-1 secretion by pericytes in a 3D brain microvessel model

Disruption of the vascular protective angiopoietin-Tie axis is common in cerebral malaria (CM) patients, who display elevated angiopoietin-2 (Ang-2) and reduced angiopoietin-1 (Ang-1) blood concentrations. The role of pericytes in CM pathogenesis remains unexplored, despite being a major source of b...

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Detalles Bibliográficos
Autores principales: Long, Rory (Autor) , Korbmacher, François (Autor) , Ronchi, Paolo (Autor) , Fleckenstein, Hannah (Autor) , Schorb, Martin (Autor) , Mirza, Waleed (Autor) , Mallorquí, Mireia (Autor) , Aguilar Lopez, Ruth (Autor) , Moncunill, Gemma (Autor) , Schwab, Yannick (Autor) , Bernabeu, Maria (Autor)
Formato: Article (Journal)
Lenguaje:inglés
Publicado: 10 November 2025
In: EMBO molecular medicine
Year: 2025, Volumen: 17, Número: 11, Pages: 3110-3138
ISSN:1757-4684
DOI:10.1038/s44321-025-00319-y
Acceso en línea:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44321-025-00319-y
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Notas de Autor:Rory K.M. Long, François Korbmacher, Paolo Ronchi, Hannah Fleckenstein, Martin Schorb, Waleed Mirza, Mireia Mallorquí, Ruth Aguilar, Gemma Moncunill, Yannick Schwab & Maria Bernabeu
Descripción
Sumario:Disruption of the vascular protective angiopoietin-Tie axis is common in cerebral malaria (CM) patients, who display elevated angiopoietin-2 (Ang-2) and reduced angiopoietin-1 (Ang-1) blood concentrations. The role of pericytes in CM pathogenesis remains unexplored, despite being a major source of brain Ang-1 secretion and evidence of pericyte damage observed in CM postmortem samples. Here, we engineered a human 3D microfluidics-based brain microvessel model containing the minimal cellular components to replicate the angiopoietin-Tie axis, human primary brain microvascular endothelial cells, and pericytes. This model replicated pericyte vessel coverage and ultrastructural interactions present in the brain microvasculature. When exposed to P. falciparum-iRBC egress products, 3D brain microvessels presented decreased Ang-1 secretion, increased vascular permeability, and minor ultrastructural changes in pericyte morphology. Notably, P. falciparum-mediated barrier disruption was partially reversed after pre-treatment with recombinant Ang-1 and the Tie-2 activator, AKB-9778. Our approach suggests a novel mechanistic role of pericytes in CM pathogenesis and highlights the potential of therapeutics that target the angiopoietin-Tie axis to rapidly counteract vascular dysfunction caused by P. falciparum.
Notas:Online veröffentlicht: 16. Oktober 2025
Gesehen am 23.03.2026
Descripción Física:Online Resource
ISSN:1757-4684
DOI:10.1038/s44321-025-00319-y

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