MicroRNA-92a/KLF2通路在切应力诱导的动脉瘤生长中的作用

Intracranial aneurysms has a high incidence. The high mortality and morbidity rate would follow when the aneurysm ruptured. The development of aneurysms is closely related with intraluminal abnormal wall shear stress. The microRNA92a（miR92a）/kruppel-like factors2（KLF-2）pathway would regulated the function of endothelium and cause arteriosclerosis. Our former research had found that KLF-2 participated the high shear stress induced vessel dilated remodeling and the aneurysm development, but the mechanism still is unknown. We planed to achieve following research: Collect the aneurysm samples and determine the relationship of miR92a/KLF-2 between human aneurysm development; Measure the expression of miR92a/KLF-2 and downstream genes, computational fluid dynamics analysis, then build up the relationship between wall shear stress and molecular expression with Co-maping technique based on rabbit aneurysm model; Administrate Simvastatin and anti-mi92a to rabbit respectively, measure the change of molecular expression and micromorphology, verificate the function and treatment target of miR92a/KLF-2 pathway in hemodynamic induced aneurysm.This study aimed at discovering the the mechanism of miR92a/KLF-2 pathway in the aneurysm development, and supporting a target of pharmaceutical therapy for intracranial aneurysms.

颅内动脉瘤发生率高，破裂致死率、致残率均高，其生长发展与管腔内异常切应力密切相关。异常切应力可通过microRNA-92a（miR-92a）/kruppel-like factors2（KLF2）通路调节血管内皮细胞功能导致动脉硬化的发生。本课题组前期研究发现KLF2可能还参与高切应力诱导的血管扩张样重构以及动脉瘤的发生与生长，但具体调控机制不清。因此我们拟借助于兔动脉瘤模型，监测不同时间点，动脉瘤预生长部位血管内皮细胞中miR-92a/KLF2以及下游靶基因的表达变化情况，给予干预手段检测微观形态学变化；通过建立血流动力学数值模拟模型，使用影像叠加技术建立切应力与KLF2表达间的关系。本研究旨在明确这一通路在切应力诱导动脉瘤发发生、发展中的作用机制，并为动脉瘤基因治疗新靶点提供理论支持。

颅内动脉瘤发生率高，破裂致死率、致残率均高，其生长发展与管腔内异常切应力密切相关。异常切应力可通过microRNA-92a（miR-92a）/kruppel-like factors2（KLF2）通路调节血管内皮细胞功能导致动脉硬化的发生。.本研究通过兔双侧颈总动脉结扎模型建立了血流动力学诱导的基底动脉动脉瘤模型。对上述通路的研究结果显示：1、兔双侧颈总动脉结扎法建立的单纯血流动力学诱导的动脉瘤模型引起的血流动力学变化最为明显，更适合做为动脉瘤研究的动物模型；2、KLF2的表达变化与血流速度变化具有一致性，二者明显正相关，提示其表达受血流动力学调控；3、miRNA-92a的表达随血流速度的增加而下降，且与血流速度的变化具有负相关性；说明miRNA-92a mRNA表达受血流动力学调控。miRNA-92a表达与KLF2表达趋势相反，二者呈显著负相关，提示miRNA-92a对KLF2表达起逆调控作用。4、辛伐他汀在25mg/kg/d的剂量，能显著上调兔双侧颈总动脉结扎组基底动脉KLF2的表达。KLF2/eNOS、ICAM-1、MMP-9途径参与了颅内动脉瘤发生。KLF2的自动表达上调可能是动脉壁的自我保护机制，辛伐他汀具有上调KLF2表达的作用，进而减少下游炎性因子ICAM-1、MMP-9的表达，促进保护性因素eNOS的表达，减轻基底动脉分叉部动脉瘤的病理改变，抑制动脉瘤的进展。.通过大样本流行病学研究发现，优势椎动脉可以引起基底动脉两侧的血流动力学因素的不对称，可能是促进椎基底动脉形态伴随年龄发生偏移与扩张的因素。优势椎动脉、高龄是VBD的独立危险因素。不同性别之间椎基底动脉形态有显著差异。.本研究结果提示，对Wilis环发育不对称中轻人群的应该给与更多的关注，血流动力学异常引起的microRNA-92a（miR-92a）/kruppel-like factors2（KLF2）通路有可能造成动脉瘤的进一步生长，他汀类药物有可能减少动脉瘤生长速度。未来应对存在血流动力学危险因素的患者是否需要提早使用他汀类药物做进一步研究。