Neurovascular development in Pten and Tsc2 mouse mutants.

Hyperactivation of the mTOR signaling pathway is linked to more than a dozen neurological 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 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 knockouts. DGC- Pten knockouts 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 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. Significance Statement Here, we examined three mouse models to determine whether mTOR hyperactivation consistently drives brain hypervascularization. Both focal loss of Pten from dentate granule cells, and widespread loss from forebrain produced larger brain structures and corresponding increases in vascular growth, but normal vessel density. By contrast, focal cortical Tsc2 lesions exhibited significantly increased vessel density. Findings indicate that hypervascularization is not characteristic of all mTOR hyperactivation models and suggest vascular changes may be driven by gene-specific effects.