The vasculome of the mouse brain.

The blood vessel is no longer viewed as passive plumbing for the brain. Increasingly, experimental and clinical findings suggest that cerebral endothelium may possess endocrine and paracrine properties – actively releasing signals into and receiving signals from the neuronal parenchyma. Hence, metabolically perturbed microvessels may contribute to central nervous system (CNS) injury and disease. Furthermore, cerebral endothelium can serve as sensors and integrators of CNS dysfunction, releasing measurable biomarkers into the circulating bloodstream. Here, we define and analyze the concept of a brain vasculome, i.e. a database of gene expression patterns in cerebral endothelium that can be linked to other databases and systems of CNS mediators and markers. Endothelial cells were purified from mouse brain, heart and kidney glomeruli. Total RNA were extracted and profiled on Affymetrix mouse 430 2.0 micro-arrays. Gene expression analysis confirmed that these brain, heart and glomerular preparations were not contaminated by brain cells (astrocytes, oligodendrocytes, or neurons), cardiomyocytes or kidney tubular cells respectively. Comparison of the vasculome between brain, heart and kidney glomeruli showed that endothelial gene expression patterns were highly organ-dependent. Analysis of the brain vasculome demonstrated that many functionally active networks were present, including cell adhesion, transporter activity, plasma membrane, leukocyte transmigration, Wnt signaling pathways and angiogenesis. Analysis of representative genome-wide-association-studies showed that genes linked with Alzheimer’s disease, Parkinson’s disease and stroke were detected in the brain vasculome. Finally, comparison of our mouse brain vasculome with representative plasma protein databases demonstrated significant overlap, suggesting that the vasculome may be an important source of circulating signals in blood. Perturbations in cerebral endothelial function may profoundly affect CNS homeostasis. Mapping and dissecting the vasculome of the brain in health and disease may provide a novel database for investigating disease mechanisms, assessing therapeutic targets and exploring new biomarkers for the CNS.

血管不再被视为大脑的被动管道。越来越多的实验和临床发现表明，脑内皮可能具有内分泌和旁分泌特性——主动向神经实质释放信号并接收来自神经实质的信号。因此，代谢紊乱的微血管可能导致中枢神经系统（CNS）损伤和疾病。此外，脑内皮可作为中枢神经系统功能障碍的传感器和整合器，向循环血液中释放可测量的生物标志物。在此，我们定义并分析脑血管组（brain vasculome）的概念，即脑内皮中基因表达模式的数据库，该数据库可与中枢神经系统介质和标志物的其他数据库及系统相联系。从小鼠的大脑、心脏和肾小球中纯化内皮细胞。提取总RNA，并在Affymetrix小鼠430 2.0微阵列上进行分析。基因表达分析证实，这些大脑、心脏和肾小球样本分别未受到脑细胞（星形胶质细胞、少突胶质细胞或神经元）、心肌细胞或肾小管细胞的污染。对大脑、心脏和肾小球之间血管组的比较表明，内皮基因表达模式具有高度的器官依赖性。对脑血管组的分析表明，存在许多功能活跃的网络，包括细胞黏附、转运体活性、质膜、白细胞迁移、Wnt信号通路和血管生成。对具有代表性的全基因组关联研究的分析表明，在脑血管组中检测到了与阿尔茨海默病、帕金森病和中风相关的基因。最后，将我们的小鼠脑血管组与具有代表性的血浆蛋白数据库进行比较，结果显示有显著重叠，这表明血管组可能是血液中循环信号的一个重要来源。脑内皮功能的紊乱可能深刻影响中枢神经系统的内稳态。绘制和剖析健康及疾病状态下的脑血管组可能为研究疾病机制、评估治疗靶点以及探索中枢神经系统的新生物标志物提供一个新的数据库。