Vascular dementia (VD) is now recognized as the second most common form of dementia after Alzheimer's disease (AD) (Cipollini et al., 2019). It appears that chronic cerebral hypoperfusion (CCH) is the common underlying pathophysiological mechanism which refers to the contribution of cognitive decline.

Recent lines of evidence suggest that disturbances to the function and structure of blood brain barrier (BBB) are a pivotal and early event that precedes premature cognitive impairment and by extension, dementia (Nation et al., 2019). The BBB is a unique microvascular structure that is made up of cerebral microvascular endothelial cells connected to an integrated vascular system by intercellular tight junctions (TJs), adherens junctions, pericytes, astrocytes, and the basement membrane. Major BBB properties are possessed by the brain vascular endothelial cells. By separating circulating blood compounds and brain, BBB acts as the brain's first line of defense to maintain homeostasis within the brain's biochemical environment (Sekaran et al., 2019).

CCH can induce an intrinsic immune response in brain tissues, which activates NOD-like receptors (NLRs), and the activation of NLRs enables the formation and activation of inflammatory vesicle complexes (Poh et al., 2022). NLRP3 is the most widely studied inflammasome, which can regulate the expression of multiple genes and play an important role in the process of inflammatory injuries in the central nervous system (CNS) (Su et al., 2019). Recently, the beneficial effects of NLPR3 inflammasome inhibition on the BBB integrity have been demonstrated after ischemic stroke or intracerebral hemorrhage (Bellut et al., 2021; Ren et al., 2018).

Piezo1 is a mechanosensitive cation channel (Coste et al., 2010), which is highly conserved throughout evolution and activated by a variety of mechanical stimuli, including shear stress, stiffness, and cyclic stress in multiple cell types, promoting Ca2+ signaling by allowing extracellular Ca2+ influx into the cell (Hu et al., 2023). Piezo1 protein is widely expressed in multiple tissues and organs, including lymphatic vessels, cardiovascular system, pulmonary system, immune cells, urinary tract and is closely implicated in lymphatic vessel development, vascular development, blood pressure regulation, erythrocyte volume homeostasis, lung function, osmoregulation, cell migration, and immune response (Lai et al., 2022; Tang et al., 2022). In addition, piezo1 has also been identified to play vital roles in regulating iron metabolism (Ma et al., 2021), mediating heart mechano-chemo transduction (Jiang et al., 2021), transducing mechanical itch (Hill et al., 2022), and regulating bone homeostasis via osteoblast-osteoclast crosstalk (Wang et al., 2020).

In the CNS, piezo1 is expressed on various cells, including neurons, astrocytes, microglial cells, oligodendrocytes, oligodendrocyte progenitor cells and endothelial cells (Qu et al., 2023; Velasco-Estevez et al., 2020, 2022) and contributes to different physiological processes. For example, piezo1 is a mechanosensory channel in capillary endothelial cells that could trigger crucial Ca2+ signals and has a profound impact on central nervous system blood flow control (Harraz et al., 2022). Moreover, astrocytes might utilize piezo1-mediated mechanotransduction mechanisms to explore the brain mechanical environment and consequently determine adult neurogenesis and cognitive behaviors (Chi et al., 2022).

However, the aberrant activation of piezo1 is associated with various pathological condition and involved in multiple pathophysiological processes of many neurological diseases. Recent evidence indicates that inhibition of piezo1 could exert neuroprotective effects in a variety of ways. For example, in response to axon injury, piezo1 channels could be activated, then induced calcium transients and the activation of calmodulin-dependent protein kinase II (CamKII), resulting in the activation of NOS and its downstream cGMP-dependent kinase Foraging or PKG to inhibit axon regeneration. While, conditional knockout of piezo1 in vivo accelerated axon regeneration (Song et al., 2019). The application of piezo1 agonist negatively regulated CNS myelination, induced demyelination and neuronal damage. On the contrary, the use of piezo1 antagonist attenuated demyelination in an ex vivo murine-derived organotypic cerebellar slice culture model induced by psychosine and lysophosphatidylcholin-induced focal demyelination model (Velasco-Estevez et al., 2020). In addition, inhibition of piezo1 with GsMTx4 might promote cell migration and proliferation of MO3.13 oligodendrocytes. In contrast, there was completely opposite effect after activating piezo1 (Velasco-Estevez et al., 2022). Previous studies have also demonstrated that the expression of piezo1 was up-regulated after cerebral ischemia/reperfusion injury in rats or oxygen-glucose deprivation/reoxygenation (OGD/R) injury in PC12 cells. Pharmacological activation of piezo1 with Yoda1 inhibited cell viability and induced apoptosis of PC12 cells after OGD/R while its inhibition with GsMTx4 led to completely opposite effects (Wang et al., 2019). Recent evidence also suggested that inhibition of piezo1 could effectively reduce the chances of arterial thrombosis and decrease cerebral infarction of stroke in hypertensive mice (Zhao et al., 2021). Qu et al. indicated that piezo1 expression significantly increased at 3 h after intracerebral hemorrhage, piezo1 suppression attenuated cerebral edema and neurological impairment, alleviated myelin loss and disorganization, and that these effects might be correlated with the inhibition of oligodendrocyte apoptosis (Qu et al., 2023). However, the role of piezo1 in CCH-induced cognitive impairment and BBB damage is unclear.

In addition, it has been suggested that NLRP3 might be a key factor contributing to the upregulation of piezo1 and was involved in facilitating spinal pain transmission after peripheral nerve injury (Li et al., 2022). Based on this background information, in this study, we examined whether cognitive impairment and BBB damage could be prevented by piezo1 inhibition in VD rats. We also determined the effects of piezo1 inhibition on the expression of NLRP3 and its down-stream factor GSDMD using an in vitro model of BBB under ischemia. Finally, we determined whether inhibiting piezo1 could prevent enhanced BBB breakdown through modulation of NLRP3 inflammasome.