Abstracts 25th Symposium Signal Transduction at the Blood-Brain Barriers 18 June 2023

A sticky situation: the influence of microvessel mechanics on cerebral malaria pathogenesis 2. Brain barriers in disease 

Matt Govendir ^{1, 2} , Rory Long ¹ , Alba Diz Muñoz ²  , Maria Bernabeu ¹ 
1  EMBL Barcelona, Barcelona, Spain; 
2  EMBL Heidelberg, Heidelberg, Germany  

Correspondence: Matt Govendir - <This email address is being protected from spambots. You need JavaScript enabled to view it.>

Cerebral malaria is the  most severe  and fatal consequence of malaria infection and occurs when Plasmodium falciparum-infected red blood cells (iRBCs) become sequestered in the brain vasculature, leading to vascular obstruction and disruption of the blood brain barrier (BBB). Interactions between iRBCs  and  cerebral  endothelial  cells  that  line  the  blood  vessels  occur  under  dynamic  mechanical conditions  due  to  changing  flow  conditions  within  vessels  and  heterogeneity  in  tissue  stiffness surrounding the vessels.  We utilise both  2D brain endothelial monolayers and  3D bio-engineered cerebral blood vessels that allow for the visualisation of iRBC binding, disruption of flow and BBB breakdown in real-time. By customising both the matrix composition, geometry and flow rate in these models we can precisely tune the mechanics of our system to observe their role in endothelial cell function and cerebral malaria pathogenesis. We reveal that when brain endothelial cells and vessels are  cultured  with  iRBC  products  they  demonstrate  increased  permeability  and  altered  adherens junctions and increased actomyosin contractility, ICAM-1 expression. Furthermore, when cultured on collagen I coated matrices or substrates, brain endothelial cells show reduced disruption by these iRBC toxins.  Our  results  demonstrate  that  both  intracellular  mechanics  (cytoskeletal  organisation)  and extracellular mechanics (cell-matrix interactions) play critical roles in regulating brain endothelial cell and BBB function in both health and disease. Further work is currently ongoing to directly measure changes  to  endothelial  monolayers  and  3D  vessel  mechanics,  via  atomic  force  and  Brillouin microscopy, when cultured on substrates of varying stiffness and after iRBC addition.