A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood¹. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

多种脑部病理严重依赖于脉管系统，脑血管疾病是全世界死亡的主要原因。然而，人类大脑脉管系统的细胞和分子结构仍未完全了解¹ 。在这里，我们对来自 68 个人类胎儿和成年患者的 117 个样本中的 606,380 个新鲜分离的内皮细胞、血管周围细胞和其他组织来源的细胞进行了单细胞 RNA 测序分析，以构建发育中的胎儿、成人对照和患病人类的分子图谱。脑血管系统。我们确定了健康胎儿和成人大脑脉管系统以及五种血管依赖性中枢神经系统（CNS）病理（包括脑肿瘤和脑血管畸形）的广泛分子异质性。我们确定了动静脉分化的改变和胎儿的重新激活，以及患病脉管系统中保守的失调基因和通路。病理内皮细胞表现出中枢神经系统特异性特性的丧失，并显示 MHC II 类分子的上调，表明中枢神经系统内皮细胞的非典型特征。细胞-细胞相互作用分析预测大量的内皮与血管周围细胞配体-受体串扰，包括免疫相关和血管生成途径，从而揭示内皮在脑神经血管单元信号网络中的核心作用。我们的单细胞大脑图谱提供了对发育中、成人/对照和患病人类大脑脉管系统的分子结构和异质性的见解，并为未来的研究提供了强有力的参考。