Graduate School of Health Sciences, Koç University, 34450 Istanbul, Turkey.
Department of Pharmaceutical Bioscience, Biomedical Centrum, Uppsala University, Sweden.
Brain Res. 2022 Nov 1;1794:148071. doi: 10.1016/j.brainres.2022.148071. Epub 2022 Sep 1.
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.
在这项研究中，我们旨在针对两种分子，转化生长因子-β（TGF-β）和动力蛋白，探索它们在高血压引起的血脑屏障（BBB）破坏中的作用。
为此，用血管紧张素（ANG）II 诱导高血压小鼠，用 TGF-β Ⅰ型受体抑制剂 SB-431542 和动力蛋白抑制剂 dynasore 进行治疗。用白蛋白-荧光素 594 评估 BBB 通透性。通过定量免疫荧光染色强度评估脑皮质和海马中 Claudin-5、 caveolin（Cav）-1、葡萄糖转运蛋白（Glut）-1 和 SMAD4 的表达变化。
ANG II 输注增加了白蛋白-荧光素 594 的 BBB 通透性，SB-431542 降低了这种通透性（P<0.01），但 dynasore 没有。在接受 dynasore 治疗的高血压动物中，Claudin-5 免疫荧光强度在大脑皮层和海马中增加，而在接受 SB-431542 治疗的高血压小鼠的大脑皮层中则降低（P<0.01）。Dynasore 和 SB-431542 均阻止了高血压动物大脑皮层和海马中 Cav-1 免疫荧光强度的增加（P<0.01）。SB-431542 和 dynasore 降低了接受 ANG II 小鼠大脑皮层和海马中的 Glut-1 免疫荧光强度（P<0.01）。SB-431542 增加了高血压动物大脑皮层中的 SMAD4 免疫荧光强度，而在海马中，SB-431542 和 dynasore 均观察到明显降低（P<0.01）。
我们的数据表明，抑制 TGFβ Ⅰ型受体可防止高血压状态下 BBB 的破坏。这些结果强调了靶向 TGFβ 信号作为一种新的治疗方式来保护高血压患者大脑的治疗潜力。
