Disrupted astrocyte-endothelial crosstalk drives hemangioblastoma-like lesions in VHL disease

Here we use advanced mouse genetics to show that mosaic deletion of Vhl in Apln+ cells leads to the formation of precursor tumour-like lesions, composed by clusters of Vhl-knockout (VhlKO) PAX2+ immature astrocytes and surrounding Vhl-wild-type (VhlWT) vessels that become malformed, resembling early-stage HBs linked to VHL disease. VhlKO astrocytes morphologically and transcriptomically resembled the reactive astrocytes characteristic of ischemic CNS injury.

They exhibited metabolic rewirement towards glycolysis and upregulation of cell growth pathways. They also expressed several secreted proangiogenic molecules like VEGF and FN1 that activate and prevent the normal maturation of neighbouring vessels, leading to VHL-HB-like lesions. VhlKO astrocytes in our model showed both structural and molecular resemblance with human HBs, having also high expression of PAX2 and FN1.