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

定义内皮 Piezo1（一种机械敏感离子通道）在为认知障碍和痴呆 (VCID) 的血管提供恢复能力方面的作用

基本信息

批准号：
10419669
负责人：
Sean P Marrelli
金额：
$ 62.02万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2023-06-30
项目状态：
已结题

项目摘要

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.

脑血管功能障碍是导致认知障碍和痴呆的一个因素在阿尔茨海默氏病 (AD) 和非 AD 病理学中，血管对认知障碍的影响和痴呆症（VCID）是一个不断发展的研究领域，涵盖了血管疾病之间的重叠和相互关系更多基础科学研究调查衰老、AD 的影响。目前需要病理学和脑血管功能。 Piezo1 是最近发现的一种机械敏感离子通道，可响应膜而控制钙流入它在多种组织中表达，但在心血管健康中起着关键作用。在外周脉管系统中，通过管腔剪切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舒张。我们提供了重要的初步数据。首次证明内皮 Piezo1 在调节脑血流 (CBF) 中发挥重要作用我们还证明，CBF 可以通过选择性递送来增强。 Piezo1 激动剂 (Yoda1) 的剂量不会改变全身血压。最近一项有趣的研究表明，外源表达人 PIEZO1 的细胞中剪切介导的 Ca2+ 流入如果这些发现与 β 淀粉样蛋白 (Ab) 单体（Ab40>Ab42）同样有效，则会被有效抑制。脑血管内源性表达的 Piezo1，这将提出一种新的机制 Ab 升高会导致 CBF 调节受损并最终发展为 VCID 我们对此进行了测试。我们发现暴露于人 Ab40 可能与小鼠脑微血管内皮细胞 (BMVEC) 相关。确实废除了流介导的 Ca2+ 反应，但这种反应对直接药理学 Piezo1 我们进一步证明，体内 CBF 对 Yoda1 的反应也完好无损。 TgSwDI 小鼠的可溶性 Ab40 和 Ab42 表达水平升高，这些令人兴奋的发现表明：而脑内皮的流动/剪切依赖性功能确实可能会因 Ab 肽升高而受损，这种功能障碍可以通过直接药理学激活 Piezo1 来“绕过”。在本提案中，我们将测试内皮 Piezo1 功能丧失（例如在条件下）的总体假设慢性流量减少或可溶性抗体升高）会导致脑血管失调和发展此外，我们还寻求通过以下方式建立为 VCID 提供弹性的策略的概念验证。使用选择性 Piezo1 激动剂在药理学上“模拟”血流介导的内皮激活。这些研究的完成将确定 EC Piezo1 在调节脑血流和这些研究将进一步探讨其功能丧失在 VCID 发展中的病理后果。为旨在恢复内皮 Piezo1 功能的新治疗策略建立科学依据在淀粉样蛋白病理学的背景下。