Single-cell analysis reveals the implication of vascular endothelial cell-intrinsic ANGPT2 in human intracranial aneurysm

AIMS: While previous single-cell RNA sequencing (scRNA-seq) studies have attempted to dissect intracranial aneurysm (IA), the primary molecular mechanism for IA pathogenesis remains unknown. Here, we uncovered the alterations of cellular compositions, especially the transcriptome changes of vascular endothelial cells (ECs), in human IA. METHODS AND RESULTS: We performed scRNA-seq to compare the cell atlas of sporadic IA and the control artery. The transcriptomes of 43 462 cells were profiled for further analysis. In general, IA had increased immune cells (T/NK cells, B cells, myeloid cells, mast cells, neutrophils) and fewer vascular cells (ECs, vascular smooth muscle cells, and fibroblasts). Based on the obtained high-quantity and high-quality EC data, we found genes associated with angiogenesis in ECs from IA patients. By EC-specific expression of candidate genes in vivo, we observed the involvement of angpt2a in causing cerebral vascular abnormality. Furthermore, an IA zebrafish model mimicking the main features of human IA was generated through targeting pdgfrb gene, and knockdown of angpt2a alleviated the vascular dilation in the IA zebrafish model. CONCLUSION: By performing a landscape view of the single-cell transcriptomes of IA and the control artery, we contribute to a deeper understanding of the cellular composition and the molecular changes of ECs in IA. The implication of angiogenic regulator ANGPT2 in IA formation and progression, provides a novel potential therapeutical target for IA interventions.