Defining the role of endothelial Piezo1, a mechanosensitive ion channel, in providing resilience to vascular contributions to cognitive impairment and dementia (VCID)

脑血管功能障碍是认知障碍和痴呆症发展的一个促成因素 在阿尔茨海默病(AD)和非AD病理中。血管对认知障碍的贡献和 痴呆症(VCID)是一个不断发展的研究领域，它涵盖了血管之间的重叠和相互关系 失调症和失调症导致痴呆。更多基础科学研究调查老龄化的影响 病理学，脑血管功能是目前所需要的。 PIEZO1是新近发现的一种机械敏感离子通道，它能通过膜调节钙离子的内流 拉伸或增加剪切力。它在多种组织中表达，但在心血管健康中起着关键作用 和疾病。在外周血管系统中，通过管腔切变或选择性激动剂激活该离子通道 促进内皮细胞内钙的增加和血管扩张。我们重要的初步数据提供了 首次证明内皮Piezo1在调节脑血流(CBF)和脑血流(CBF)中发挥重要作用 有助于微血管的稳定。我们还证明，CBF可以通过提供选择性的 PIEZO1激动剂(Yoda1)，剂量不改变全身血压。 最近一项耐人寻味的研究表明，剪切介导的钙离子内流外源表达人PIEZO1的细胞 被淀粉样β(Ab)单体(Ab40和GT；AB42)有效抑制。如果这些发现同样适用于 在脑血管中内源性表达Piezo1，这将提示一种新的机制，通过 抗体升高导致CBF调节受损，最终导致VCID的发生。我们测试了这个 与小鼠脑微血管内皮细胞(BMVECs)的可能性。我们发现接触人类AB40病毒 确实取消了流介导的钙反应，但这种对直接药理学Piezo1的反应 激活状态保持不变。我们进一步证明，体内对Yoda1的CBF反应也是完整的 TgSwDI小鼠，表达升高的可溶性Ab40和AB42水平。这些具有挑衅性的发现表明 虽然脑内皮细胞的血流/剪切依赖功能确实可能受到升高的抗体多肽的损害， 这种功能障碍可以通过Piezo1的直接药理激活而被“绕过”。 在这项提议中，我们将检验内皮Piezo1功能丧失(如在条件下)的总体假设 慢性血流量减少或可溶性抗体升高)导致脑血管调节失调和发展 是VCID的。此外，我们寻求为战略建立概念验证，通过以下方式提供对VCID的弹性 用选择性的Piezo1激动剂在药理学上“模仿”血流介导的内皮激活。 这些研究的完成将确立EC Piezo1在调节脑血流和 在VCID的发展过程中其功能丧失的病理后果。这些研究将进一步 建立旨在恢复内皮Piezo1功能的新治疗策略的科学合理性 在淀粉样蛋白病理的背景下。

Cerebrovascular dysfunction is a contributing factor to the development of cognitive impairment and dementia in both Alzheimer’s disease (AD) and in non-AD pathologies. Vascular contributions to cognitive impairment and dementia (VCID) is an evolving field of study which covers the overlap and interrelationship between vascular disorders and disorders leading to dementia. More basic science research investigating the impact of aging, AD pathology, and cerebrovascular function is currently needed. Piezo1 is a recently identified mechanosensitive ion channel that gates calcium influx in response to membrane stretch or increased shear forces. It is expressed in multiple tissues, but plays a critical role in cardiovascular health and disease. In the peripheral vasculature, activation of this ion channel by luminal shear or by a selective agonist promotes increased endothelial intracellular calcium and vasodilation. Our significant preliminary data provide the first demonstration that endothelial Piezo1 plays an important role in regulating cerebral blood flow (CBF) and contributes to microvascular stability. We also demonstrate that CBF can be enhanced by delivery of a selective Piezo1 agonist (Yoda1) at doses that do not alter systemic blood pressure. An intriguing recent study showed that shear-mediated Ca2+ influx in cells exogenously expressing human PIEZO1 was potently inhibited by amyloid beta (Ab) monomers (Ab40>Ab42). If these findings are similarly valid with endogenously-expressed Piezo1 within the cerebral vasculature, it would suggest a new mechanism by which elevated Ab contributes to impaired CBF regulation and the eventual development of VCID. We tested this possibility with mouse brain microvascular endothelial cells (BMVECs). We found that exposure to human Ab40 indeed abolished the flow-mediated Ca2+ response, but that responsiveness to direct pharmacological Piezo1 activation remained intact. We further demonstrated that the in vivo CBF response to Yoda1 was also intact in TgSwDI mice which express elevated levels of soluble Ab40 and Ab42. These provocative findings suggest that while flow/shear-dependent function of cerebral endothelium may indeed be impaired by elevated Ab peptides, this dysfunction may be “bypassed” by direct pharmacological activation of Piezo1. In this proposal, we will test the overall hypothesis that loss of endothelial Piezo1 function (such as in conditions of chronically reduced flow or elevated soluble Ab) leads to cerebrovascular dysregulation and the development of VCID. In addition, we seek to establish proof-of-concept for a strategy to provide resilience to VCID by pharmacologically “mimicking” flow-mediated endothelial activation with selective Piezo1 agonists. Completion of these studies will establish a vital role of EC Piezo1 in the regulation of cerebral blood flow and the pathological consequences of its functional loss in the development of VCID. These studies will further establish the scientific justification for new therapeutic strategies aimed at restoring endothelial Piezo1 function in the context of amyloid pathology.