Notch Signaling in Pericytes during Central Nervous System Vascular Development and Pathology

Pericytes are perivascular cells of microvessels. In the central nervous system (CNS), they have critical functions in vascular development and in blood-brain and blood-retinal barrier regulation. Pericyte loss and/or dysfunction is associated with aberrant angiogenesis, impaired vessel remodeling, and breakdown of CNS barriers. Arteriovenous malformations (AVMs) and germinal matrix-intraventricular hemorrhage are some pathologies associated with pericyte loss and/or dysfunction. Our aim is to further our understanding of pericyte-endothelial communication and how it may contribute to CNS pathologies. Notch signaling is crucial for vascular development and has been proposed to regulate critical pericyte functions. We hypothesized that Notch signaling in pericytes during angiogenesis regulates pericyte homeostasis and promotes vessel stability in the CNS. We inhibited Notch signaling perinatally to study retinal angiogenesis and embryonically to study brain angiogenesis. In the retina, the deficiency of Notch signaling reduced pericyte viability and proliferation, leading to pericyte loss. This resulted in improper vascular remodeling, vessel enlargement, and AVM development. Conversely, the constitutive activation of Notch signaling promoted pericyte coverage and maturation and ameliorated vascular abnormalities in an AVM mouse model of hereditary hemorrhagic telangiectasia. Deficiency of Notch signaling in the embryonic brain revealed region-specific pericyte loss in the germinal matrix (GM). This led us to investigate whether there were differences in pericytes in the GM and the cortex in wild-type mice. We observed similar pericyte coverage, but differential marker expression between the two regions, underscoring the existence of pericyte heterogeneity in the angiogenic brain. Further, the loss of Notch signaling in the embryonic brain showed that pericyte loss was detected early in GM angiogenesis, followed by impaired vessel morphogenesis at later time-points. Our combined studies highlight the importance that Notch signaling has in regulating pericyte survival and proliferation, and how it might contribute to the pathogenesis of vascular diseases in the CNS.