TY - JOUR
KW - 3D Brain Microvascular Models
KW - AKB-9778
KW - Angiopoietin–Tie Axis
KW - Cerebral Malaria
KW - Pericytes
AU - Rory K. M. Long
AU - François Korbmacher
AU - Paolo Ronchi
AU - Hannah Fleckenstein
AU - Martin Schorb
AU - Waleed Mirza
AU - Mireia Mallorquí
AU - Ruth Aguilar
AU - Gemma Moncunill
AU - Yannick Schwab
AU - Maria Bernabeu
AB - 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.
BT - EMBO Molecular Medicine
DA - 2025-11-01
DO - 10.1038/s44321-025-00319-y
IS - 11
LA - en
N2 - 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.
PY - 2025
SP - 3110
EP - 3138
T2 - EMBO Molecular Medicine
TI - Plasmodium falciparum impairs Ang-1 secretion by pericytes in a 3D brain microvessel model
UR - https://doi.org/10.1038/s44321-025-00319-y
VL - 17
Y2 - 2026-04-06
SN - 1757-4684
ER -