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 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.