Targeting the blood–brain barrier disruption in hypertension by ALK5/TGF-В type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore

Abstract

Introduction: In this study, we aimed to target two molecules, transforming growth factor-beta (TGF-beta) and dynamin to explore their roles in blood-brain barrier (BBB) disruption in hypertension. Methods: For this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-beta type I receptor, and dynasore, an inhibitor of dynamin. Albumin-Alexa fluor 594 was used to assess BBB permeability. The alterations in the expression of claudin-5, caveolin (Cav)-1, glucose transporter (Glut)-1, and SMAD4 in the cerebral cortex and the hippocampus were evaluated by quantification of immunofluorescence staining intensity.Results: ANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB431542 (P < 0.01), but not by dynasore. In hypertensive animals treated with dynasore, claudin-5 immunofluorescence intensity increased in the cerebral cortex and hippocampus while it decreased in the cerebral cortex of SB-431542 treated hypertensive mice (P < 0.01). Both dynasore and SB-431542 prevented the increased Cav-1 immunofluorescence intensity in the cerebral cortex and hippocampus of hypertensive animals (P < 0.01). SB431542 and dynasore decreased Glut-1 immunofluorescence intensity in the cerebral cortex and hippocampus of mice receiving ANG II (P < 0.01). SB-431542 increased SMAD4 immunofluorescence intensity in the cerebral cortex of hypertensive animals, while in the hippocampus a significant decrease was noted by both SB-431542 and dynasore (P < 0.01).Conclusion: Our data suggest that inhibition of the TGF beta type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGF beta signaling as a novel treatment modality to protect the brain of hypertensive patients.