Brain arteriovenous malformation (AVM) is a disease characterized by multiple vascular abnormalities, including arteriovenous (AV) shunting – formation of direct connections between arteries and veins at the expense of capillary networks. Blood flows rapidly through these abnormal connections; thus, these vessels are prone to rupture, which can lead to devastating outcomes. Treatment methods for brain AVM are limited; therefore, it is important to understand the mechanisms of disease pathogenesis in order to develop novel therapies. Using genetically engineered mice, we have previously shown that deletion of Rbpj from endothelial cells – cells that form the inner lining of blood vessels – during the developmental period just after birth, leads to characteristic AVM features.
Using our AVM model, I tested the hypothesis that, following deletion of endothelial Rbpj, pericyte coverage of endothelium is affected. Pericytes are specialized vascular cells that enwrap capillaries and are important for the development and maintenance of the vascular system. By analyzing pericyte area, endothelial area, and percent endothelium covered by pericytes in control and Rbpj-mutant mice, I found increased areas of pericytes and endothelium in select regions of the brain and at select timepoints. I also determined that the percent endothelium covered by pericytes was not significantly different between mutants and controls. These results suggest that endothelial Rbpj regulates total pericyte and endothelial area in the brain, and in Rbpj-mediated brain AVM, pericytes keep pace with the pathological increase of endothelium. The increased pericyte area may result from a variety of changes, including increased pericyte cell number and/or alterations in pericyte morphology. Results showed, in mutant vs. control brains, that pericyte number may be increased but that pericyte proliferation was not increased, suggesting another mechanism of pericyte recruitment. Additionally, altered pericyte morphology was observed in mutant brains as compared to controls. Collectively, these results challenge the field’s working hypothesis that brain AVM is associated with pericyte reductions, which may contribute to vessel instability. These results also define a novel role for Rbpj in postnatal brain endothelium: to prevent pathogenic pericyte expansion and to maintain pericyte morphology.