02228nas a2200337   4500000000100000000000100001008004100002260001500043653003400058653001300092653002800105653002100133653001400154100002000168700002500188700001700213700002400230700001800254700001700272700002200289700001700311700002000328700001900348700001900367245009500386856004700481300001400528490000700542520132700549022001401876       2025                            d  c2025-11-0110a3D Brain Microvascular Models10aAKB-977810aAngiopoietin–Tie Axis10aCerebral Malaria10aPericytes1 aRory K. M. Long1 aFrançois Korbmacher1 aPaolo Ronchi1 aHannah Fleckenstein1 aMartin Schorb1 aWaleed Mirza1 aMireia Mallorquí1 aRuth Aguilar1 aGemma Moncunill1 aYannick Schwab1 aMaria Bernabeu00aPlasmodium falciparum impairs Ang-1 secretion by pericytes in a 3D brain microvessel model  uhttps://doi.org/10.1038/s44321-025-00319-y  a3110-31380 v173 aDisruption 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.  a1757-4684