Activated endothelial cells induce a distinct type of astrocytic reactivity

Injured endothelial cells are shown to induce an A1 phenotype in astrocytes, characterized by a genetic signature associated with extracellular matrix remodeling factors (e.g. decorin and vascular Ass deposits). Reactive astrogliosis is a universal response of astrocytes to abnormal events and injuries. Studies have shown that proinflammatory microglia can polarize astrocytes (designated A1 astrocytes) toward a neurotoxic phenotype characterized by increased Complement Component 3 (C3) expression. It is still unclear if inflammatory stimuli from other cell types may also be capable of inducing a subset of C3(+) neurotoxic astrocytes. Here, we show that a subtype of C3(+) neurotoxic astrocytes is induced by activated endothelial cells that is distinct from astrocytes activated by microglia. Furthermore, we show that endothelial-induced astrocytes have upregulated expression of A1 astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial-induced astrocytes are Decorin-positive and are associated with vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings demonstrate the existence of potentially extensive and subtle functional diversity of C3(+)-reactive astrocytes.

Automated summary

Injured endothelial cells can induce neurotoxic astrocytes characterized by genetic signatures associated with extracellular matrix remodeling. These astrocytes, activated by endothelial cells, are distinct from those activated by other cell types and are associated with vascular amyloid deposits.