Plasmodium falciparum disruption of pericyte angiopoietin-1 secretion contributes to barrier breakdown in a 3D brain microvessel model

Disruption of the vascular protective angiopoietin-Tie axis is common in cerebral malaria (CM) patients, with 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 in CM postmortem samples. Here we engineered a 3D microfluidics-based microvessel model containing both 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. Our approach suggests a novel mechanistic role of pericytes in CM pathogenesis and highlights the importance of the angiopoietin-Tie axis in vascular dysfunction caused by P. falciparum .