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

Muge Atis, Uğur Akcan, Deniz Altunsu, Ecem Ayvaz, Canan Uğur Yılmaz, Deniz Sarıkaya, Arzu Temizyürek, Bülent Ahıshalı, Hélène Girouard, Mehmet Kaya

Brain research 2022 Nov 01

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In this study, we aimed to target two molecules, transforming growth factor-beta (TGF-β) and dynamin to explore their roles in blood-brain barrier (BBB) disruption in hypertension. For this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-β 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. ANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB-431542 (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). SB-431542 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). Our data suggest that inhibition of the TGFβ type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGFβ signaling as a novel treatment modality to protect the brain of hypertensive patients. Copyright © 2022. Published by Elsevier B.V.

Citation

Muge Atis, Uğur Akcan, Deniz Altunsu, Ecem Ayvaz, Canan Uğur Yılmaz, Deniz Sarıkaya, Arzu Temizyürek, Bülent Ahıshalı, Hélène Girouard, Mehmet Kaya. Targeting the blood-brain barrier disruption in hypertension by ALK5/TGF-Β type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore. Brain research. 2022 Nov 01;1794:148071