Chronic cerebral hypoperfusion (CCH) plays a critical role in the onset and progression of vascular dementia (VD), which is now recognized as the second most common form of dementia after Alzheimer's disease (AD). The mechanosensitive piezo1 channel has been identified to play important roles in several neurological disorders. However, the roles and possible mechanisms of piezo1 in CCH-induced cognitive decline and blood brain barrier (BBB) disruption, as well as the underlying mechanisms remain elusive. In this study, the CCH model was established by bilateral common carotid artery occlusion in rats and by oxygen and glucose deprivation/reoxygenation (OGD/R) in bEnd.3 cells. The results demonstrated that the antagonist of piezo1 GsMTx4 ameliorated CCH-induced cognitive dysfunction and mitigated cerebral edema. Furthermore, this study indicated that GsMTx4 improved the permeability and integrity of BBB and protected cerebral microvasculature after CCH. In vitro, GsMTx4 improved cell viability, promoted the ability of cell motility and migration, and inhibited the degradation of BBB integrity-related proteins by inhibiting NLRP3 inflammasome activation. In addition, NLRP3 agonist abolished the beneficial effects of GsMTx4. Collectively, our results demonstrate that piezo1 might be involved in CCH-induced cognitive impairment and BBB damage, which may be at least partially mediated through regulation of NLRP3 inflammasome.

中文翻译：

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抑制piezo1可预防慢性脑灌注不足引起的认知障碍和血脑屏障破坏

慢性脑灌注不足 (CCH) 在血管性痴呆 (VD) 的发病和进展中起着至关重要的作用，血管性痴呆 (VD) 目前被认为是继阿尔茨海默病 (AD) 后第二常见的痴呆形式。机械敏感的piezo1通道已被确定在多种神经系统疾病中发挥重要作用。然而，piezo1 在 CCH 诱导的认知衰退和血脑屏障 (BBB) 破坏中的作用和可能机制以及潜在机制仍然难以捉摸。在本研究中，通过大鼠双侧颈总动脉闭塞和bEnd.3细胞缺氧和缺糖/复氧（OGD/R）建立CCH模型。结果表明，piezo1 GsMTx4 拮抗剂可改善 CCH 诱导的认知功能障碍并减轻脑水肿。此外，这项研究表明，GsMTx4 改善了 CCH 后 BBB 的通透性和完整性，并保护了脑微血管。在体外，GsMTx4通过抑制NLRP3炎性体激活，提高细胞活力，促进细胞运动和迁移能力，并抑制BBB完整性相关蛋白的降解。此外，NLRP3 激动剂消除了 GsMTx4 的有益作用。总的来说，我们的结果表明，piezo1 可能参与 CCH 诱导的认知障碍和 BBB 损伤，这可能至少部分是通过 NLRP3 炎性体的调节介导的。