A Shared Disease-Associated Endothelial Program in Glioblastoma Neovasculature and Brain Arteriovenous Malformation with Prognostic Association in Glioma

Abstract

Objective: Glioblastoma (GBM) and brain arteriovenous malformation (bAVM) are distinct cerebrovascular pathologies defined by aberrant vasculature. We investigated whether brain endothelial cells (ECs) in both conditions converge on a common transcriptional program carrying prognostic value in diffuse glioma. Methods: We reanalyzed single-cell transcriptomes from 163,802 Raw FACS-purified human brain ECs across GBM, bAVM, lower-grade glioma (LGG), and non-pathological controls. Using patient-level pseudo-bulk differential expression, we derived a 100-gene shared module, assessed its stability (leave-one-patient-out, bootstrap), and adjusted for endothelial composition, age, and sex. Replication was performed in an independent single-cell EC cohort, bulk datasets, and 669 TCGA gliomas. Results: Patient-level pseudobulk analysis identified a 100-gene disease-associated module (led by ESM1, ADAMTS5, PLVAP). Independently derived GBM-up and bAVM-up gene sets shared 605 genes (p = 7.3 × 10-293). Module induction persisted within matched endothelial subtypes across both diseases, showing a graded response: control < LGG < bAVM < GBM (p = 1.4 × 10-9). In patient-level models, the GBM effect survived full covariate adjustment (p = 0.0067), whereas the bAVM effect attenuated due to compositional shifts. The module replicated in independent single-cell (p = 4.8 × 10-19) and bulk glioma cohort, and higher expression independently predicted shorter overall survival in TCGA gliomas (adjusted HR = 1.38, p = 1.1 × 10-6). Conclusion: GBM and bAVM share a common endothelial transcriptional state driven by vascular remodeling and inflammatory angiogenesis. In GBM, this state represents intrinsic endothelial reprogramming with significant prognostic value, whereas in bAVM it is largely linked to compositional changes.