PDGF-BB/PDGFRβ通路及其调控的microRNAs介导的血脑屏障改变在血管性认知损害中的作用和机制研究

慢性脑低灌注及其所致的血管性认知损害（VCI）是AD和VaD共有的重要病理基础。我们前期研究发现，VCI早期海马区血脑屏障（BBB）通透性增加与认知损害相关，但BBB破坏介导VCI的分子机制尚未阐明。血小板源性生长因子-B（PDGF-BB）与其受体PDGFRβ结合对维持BBB完整性及脑血流调节具有重要作用，microRNAs能够调控BBB内皮细胞紧密连接蛋白表达。因此，我们推测，PDGF-BB/PDGFRβ通路激活调控的下游microRNA表达能增强BBB完整性并减轻循环障碍所致的VCI。本研究拟建立慢性脑低灌注动物模型和BBB细胞模型，过表达内皮细胞PDGF-BB，并以PDGFRβ受体抑制剂及microRNA质粒干预，采用分子病理和激光多普勒等方法动态观察BBB与脑血流变化的关系，探讨PDGF-BB/PDGFRβ通路调控的下游microRNA在慢性脑低灌注中对BBB和认知功能的作用机制。

Chronic cerebral hypoperfusion (CCH) and CCH induced vascular cognitive impairment (VCI) are the common pathological basis of AD and VaD. In our previous study, we found that the increased permeability of BBB in hippocampus at the early stage of VCI was related to cognitive impairment. However, the pathological mechanism of BBB disruption mediated VCI has not been elucidated. Platelet derived growth factor-B (PDGF-BB) secreted by endothelial and PDGFRβ receptor of pericyte play an important role in maintaining the integrity of BBB and regulation of cerebral blood flow. MicroRNAs could regulate endothelial tight junction protein expression. Therefore, we hypothesized that the expression of downstream microRNA regulated by PDGF-BB/PDGFRβ pathway can enhance BBB integrity and alleviate VCI induced by chronic cerebral hypoperfusion. The aim of this study was to establish a rat model of chronic cerebral hypoperfusion and BBB cell model. PDGF-BB was overexpressed by recombinant adeno-associated virus expressed on cerebral endothelial cell, PDGFRβ was inhibited by PDGFRβ receptor inhibitor and microRNA was inhibited by microRNA interference plasmid. Cerebral blood flow was dynamically observed by laser Doppler and BBB was measured by western blot, transmission electron microscope, evans blue and confocal laser scanning microscope in order to explore the mechanism of microRNA in the downstream of PDGF-BB/PDGFRβ pathway on BBB and cognitive function induced by chronic cerebral hypoperfusion.