Neurovascular Development in Pten and Tsc2 Mouse Mutants

Hyperactivation 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 of Pten or Tsc2, both mTOR negative regulators, alters brain vasculature in three mouse models: one with Pten loss restricted to hippocampal dentate granule cells [DGC-Pten knock-outs (KOs)], a second with widespread Pten loss from excitatory forebrain neurons (FB-Pten KOs) and a third with focal loss of Tsc2 from cortical excitatory neurons (f-Tsc2 KOs). Total hippocampal vessel length and volume per dentate gyrus were dramatically increased in DGC-Pten knock-outs. DGC-Pten knock-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-Pten KOs recapitulated the findings in the more restricted DGC-Pten KOs, with increased vessel area, but preserved vessel density. FB-Pten KOs did, however, exhibit elevated levels of the angiogenic factor VegfA. In contrast to findings with Pten, focal loss of Tsc2 from cortical excitatory neu-rons 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 regula-tory genes exert distinct effects on angiogenesis.

Automated summary

Hyperactivation of the mTOR signaling pathway is associated with various neurologic diseases, while the effects on brain vasculature differ depending on the loss of specific mTOR negative regulators. Loss of Pten or Tsc2 in mouse models leads to altered vessel characteristics, but the extent and nature of the changes vary. Pten loss results in increased vessel length and volume in specific brain regions, while Tsc2 loss causes localized increase in vessel density.