Cerebrovascular vulnerability and fibrosis in human brain aneurysms.

Brain aneurysms are a cerebrovascular disease that results in a severe type of stroke. The cell-specific molecular pathology underlying their formation and rupture is unknown. Here we profile 227,663 neurovascular cells, including 52,946 aneurysmal cells, from a total of 14 adult human brain aneurysms and 11 control vessels. Our atlas of human brain aneurysms, as well as cell-resolution spatial transcriptomics, revealed that pathological cerebrovascular remodeling occurs with the loss of structurally supportive smooth muscle cells and the emergence of activated perivascular fibroblasts, which re-populate the vascular wall and express multiple genes linked to aneurysm risk. Fibrotic changes coincide with fibroblast-myeloid cell signaling pathways and an influx of specialized macrophages that are rarely detected in non-aneurysmal cerebrovasculature and that express destabilizing vascular cell programs. Thus, we reveal an unrecognized interplay between cerebrovascular fibrosis and myeloid inflammation during disease progression, substantially advancing our understanding of the cellular drivers and mechanisms underlying this devastating cerebrovascular disease that will inform translational development.