子痫前期出生子代脐动脉血管中FN1异常表达的分子机制和远期效应研究

The gamete and embryo-fetal origins of vascular diseases have gained much attention by clinical and basic researchers. Epidemiological studies have suggested an association of intrauterine adverse environment in pre-eclampsia (PE) and their offspring with vascular dysfunction, which would increase the risk of cardiovascular disease. However, the mechanisms involved remain to be established. Our recent findings have discovered that fibronectin 1 (FN1), related to vascular function, was up-regulated in umbilical artery of pre-eclampsia offspring. Previous studies have indicated that the up-regulation of FN1 was related to the pathological conditions such as atherosclerosis. In the present project, we will explore the molecular mechanism and long-term effect of the up-regulation of FN1 in three levels including the clinical samples, cell lines, and animal model. We will analyze the promoter methylation of FN1 gene in umbilical artery of PE offspring; reveal the role of PE-related factors (renin, angiotensin) in regulating aberrant FN1 methylation; detect the influence of aberrant FN1 expression on vascular cell growth and function; disclose the association among PE-related factors, aberrant FN1 expression, and the risk of vascular disease in adulthood of PE offspring. We are in the hope of revealing the molecular mechanism and long-term effects of aberrant FN1 expression induced by PE-related factors in their offspring. Furthermore, our finding may also provide theory basis for clinical controlling vascular disease risk in PE offspring at the source.

配子和胚胎源性血管性疾病是全世界备受重视的研究领域。流行病学研究显示，子痫前期（PE）所造成的宫内不良环境可导致子代血管功能出现不同程度的紊乱，从而增加其高发心血管疾病的风险，但其分子机制仍有待研究。本实验室前期发现PE患者子代脐动脉血管中与血管功能相关的FN1蛋白表达上调，而已知FN1表达上调与动脉粥样硬化等病理状况密切相关。本项目将在临床样本、细胞系和动物模型三个层面对PE子代血管FN1表达上调的机制和远期效应进行研究。检测PE子代血管FN1基因的甲基化状态，探讨PE相关因子（肾素、血管紧张素）在FN1基因异常甲基化中的调控作用；检测FN1异常表达对血管细胞生长和功能的影响；探讨PE相关因子和FN1异常表达对PE大鼠子代成年血管功能的远期影响。研究结果将揭示PE相关因子所致子代血管FN1表达异常和远期效应的分子机制，为临床实践中降低PE对子代血管性疾病发生风险和源头控制提供理论基础。

胚胎源性血管性疾病是备受重视的研究领域。子痫前期（PE）所造成的宫内不良环境可导致子代血管功能出现不同程度的紊乱，从而增加其高发心血管疾病的风险，但其分子机制仍有待阐明。项目实施过程中，我们开展了PE患者子代脐血管中FN1表达异常的机制探讨；通过蛋白质组学技术鉴定PE和OHSS出生子代脐血管中的差异表达蛋白质；通过全基因组甲基化谱检测技术探索PE出生子代脐血管内皮细胞中的差异甲基化基因；并建立PE大鼠模型，观察其子代远期效应。研究结果显示：PE患者子代脐动脉血管中FN1异常表达上调与其启动子区域低甲基化有关；成功鉴定出的PE和OHSS子代脐血管差异表达蛋白质功能与心血管疾病发生密切相关；PE子代全基因组水平差异DNA甲基化基因涉及内皮细胞分化功能调节；PE大鼠子代远期血管功能有显著改变。该研究鉴定出PE出生子代脐血管中差异表达蛋白质和差异甲基化基因，为从源头控制PE出生子代的血管性疾病发生提供潜在分子靶点。