Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.

Piezo1 通过将流体流动产生的机械信号转换为生物过程来调节血管系统的多个方面。在这里，我们发现Piezo1对于脑膜淋巴管的正常发育和功能是必需的，并且通过转基因过度表达或用化学激动剂Yoda1处理来激活Piezo1足以通过改善淋巴吸收和运输来增加脑脊液（CSF）流出。脑脊液异常积聚常导致脑积水和脑室扩大，目前缺乏有效的治疗方法。我们发现唐氏综合症小鼠模型中的脑膜淋巴管发育不完全且形成异常。在患有脑积水或唐氏综合症的小鼠中，淋巴管中 Piezo1 的选择性过度表达或 Yoda1 的全身给药可导致病理性脑脊液积聚、脑室扩大和其他相关疾病症状显着减少。总之，我们的研究强调了 Piezo1 介导的淋巴机械转导在维持脑液引流中的重要性，并将 Piezo1 确定为治疗脑脊液过度积聚和脑室扩大的有前途的治疗靶点。