Gallego-Delgado, JulioRodriguez, Ana et alFernández Arias, Cristina2025-01-102025-01-102016-10-01Gallego-Delgado J, Basu-Roy U, Ty M, Alique M, Fernandez-Arias C, Movila A, Gomes P, Weinstock A, Xu W, Edagha I, Wassmer SC, Walther T, Ruiz-Ortega M, Rodriguez A. Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria. J Clin Invest. 2016 Oct 3;126(10):4016-4029. doi: 10.1172/JCI87306. Epub 2016 Sep 19. PMID: 27643439; PMCID: PMC5096829.10.1172/JCI87306https://hdl.handle.net/20.500.14352/113782Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://doi.org/10.1172/JCI87306https://www.jci.org/articles/view/87306restricted access612.017Ciencias Biomédicas32 Ciencias Médicas