社会支持通过诱导心脏ANP分泌促进缺血性脑卒中后神经血管再生和功能恢复的机制研究

Social support (SS) could lessen post-stroke depression (PSD) and post-stroke anxiety (PSA). And it is one of the most important social psychological factors influencing functional recovery after cerebral ischemic stroke (CIS). However, the underlying mechanisms are unclear. Our recent data showed that SS could lessen PSD and PSA after CIS. Our preliminary results showed for the first time that SS could increase the secretion of atrial natriuretic peptide (ANP) from atrial muscle cells, and ANP could bind to the membranes of ependymal cells (ECs) and choroid plexus epithelial cells (CPECs). According to our these findings, combined with recent reports that ECs/CPECs express natriuretic peptide receptors (NPRs) on the cell membrane and could secret TGF-β which could promote post-stroke neurovascular regeneration, and our preliminary results found that exogenous administration of ANP could increase the protein expression of TGF-β in the ischemic brain during stroke recovery, we hypothesize that SS increases the secretion of ANP through lessening PSD and PSA, which binds to NPRs on the membranes of ECs/CPECs and promotes the secretion of TGF-β from ECs/CPECs, and ultimately promotes neurovascular regeneration and functional recovery after CIS. This project intends to use various experimental technologies in vivo and in vitro to explore the effects of SS on the functional recovery after CIS, and to provide experimental basis for the identification of new therapeutic strategies and potential therapeutic targets for the treatment of CIS in the delayed phases of stroke recovery.

社会支持（SS）可减轻卒中后抑郁（PSD）和焦虑（PSA），是影响缺血性脑卒中（CIS）神经功能恢复最重要心理因素之一，但机制不明。我们前期研究证实SS可减轻PSD和PSA；我们预实验首次发现：通过采用动物配对饲养模型在CIS恢复期发现，SS可增加心房肌细胞合成和分泌心房钠尿肽（ANP），ANP可与侧脑室壁室管膜细胞（ECs）和脉络丛上皮细胞（CPECs）胞膜结合。结合新近发现ECs/CPECs胞膜表达钠尿肽受体（NPRs）且可分泌促神经血管再生的TGF-β的报道以及我们预实验外源性ANP可增加CIS恢复期脑组织TGF-β表达，提出假设：SS通过减轻PSD和PSA，增加CIS恢复期ANP分泌，作用于侧脑室壁ECs/CPECs的NPRs，刺激TGF-β表达，促进功能恢复。本课题拟采用多种实验技术，在整体和细胞水平阐明SS在CIS恢复期重要作用，并为寻找恢复期治疗的新策略和新靶点提供实验依据。

社会支持的缺失可诱导并加重脑卒中患者卒中后抑郁（PSD）和焦虑（PSA）。PSD和PSA是影响缺血性脑卒中恢复期神经血管再生和功能恢复的最重要心理因素之一。通过体外原代培养缺血性脑卒中恢复期室管膜和脉络丛上皮细胞，我们离体研究发现，ANP可直接促进体外培养的是室管膜和脉络丛上皮细胞合成和分泌TGF-β。通过建立小鼠大脑中动脉栓塞（MCAO）模型模拟缺血性脑卒中，小鼠在MCAO前2周开始与去卵巢雌性小鼠开始配对饲养和雄性小鼠单独饲养分别模拟社会支持和社会隔离，我们在体研究发现，社会支持的缺失（即社会隔离）可促进PSD和PSA发生，减少缺血性脑卒中恢复期心脏合成和分泌ANP，作用于室管膜和脉络丛上皮细胞NPR-A的ANP减少导致室管膜和脉络丛的TGF-β表达减少，减少Tregs和细胞因子IL-10，从而抑制Tregs对免疫抑制微环境的构建，抑制恢复期神经再生和功能恢复。. 我们的研究表明了PSD对缺血性脑卒中恢复期心脏合成和分泌ANP具有重要调节作用，ANP通过Tregs介导的缺血侧脑组织免疫抑制微环境构建在缺血性脑卒中后神经再生和功能恢复中起重要作用，通过对恢复期ANP干预（如重组人ANP蛋白）可望为缺血性脑卒中后神经血管再生和功能恢复提供新策略。