Neurovascular Development inPtenandTsc2Mouse Mutants

Abstract

AbstractHyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is linked to more than a dozen neurologic diseases, causing a range of pathologies, including excess neuronal growth, disrupted neuronal migration, cortical dysplasia, epilepsy and autism. The mTOR pathway also regulates angiogenesis. For the present study, therefore, we queried whether loss ofPtenorTsc2, both mTOR negative regulators, alters brain vasculature in three mouse models: one withPtenloss restricted to hippocampal dentate granule cells [DGC-Ptenknock-outs (KOs)], a second with widespreadPtenloss from excitatory forebrain neurons (FB-PtenKOs) and a third with focal loss ofTsc2from cortical excitatory neurons (f-Tsc2KOs). Total hippocampal vessel length and volume per dentate gyrus were dramatically increased in DGC-Ptenknock-outs. DGC-Ptenknock-outs had larger dentate gyri overall, however, and when normalized to these larger structures, vessel density was preserved. In addition, tests of blood-brain barrier integrity did not reveal increased permeability. FB-PtenKOs recapitulated the findings in the more restricted DGC-PtenKOs, with increased vessel area, but preserved vessel density. FB-PtenKOs did, however, exhibit elevated levels of the angiogenic factor VegfA. In contrast to findings withPten, focal loss ofTsc2from cortical excitatory neurons produced a localized increase in vessel density. Together, these studies demonstrate that hypervascularization is not a consistent feature of mTOR hyperactivation models and suggest that loss of different mTOR pathway regulatory genes exert distinct effects on angiogenesis.