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Neurovascular Development in Pten and Tsc2 Mouse Mutants
Mary Dusing1, Candi L LaSarge1,2,3,4, Angela White5
1Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Eneuro
|February 9, 2023
Summary
Loss of Pten or Tsc2 in mouse models of neurologic disease alters brain vasculature. While Pten loss increases vessel size, Tsc2 loss increases vessel density, showing distinct effects on angiogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Vascular Biology
Background:
- Hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is implicated in numerous neurologic diseases.
- The mTOR pathway plays a role in neuronal development and angiogenesis.
- Loss of mTOR negative regulators like Pten and Tsc2 can lead to aberrant mTOR signaling.
Purpose of the Study:
- To investigate the effects of Pten or Tsc2 loss on brain vasculature in mouse models.
- To determine if mTOR pathway dysregulation consistently leads to hypervascularization.
- To compare the distinct vascular effects of Pten versus Tsc2 loss.
Main Methods:
- Generated three mouse models: DGC-Pten knock-outs (KOs), FB-Pten KOs, and f-Tsc2 KOs.
- Analyzed hippocampal and cortical vasculature, including vessel length, volume, and density.
- Assessed blood-brain barrier integrity and measured levels of the angiogenic factor VegfA.
Main Results:
- DGC-Pten KOs showed increased hippocampal vessel length and volume, but preserved vessel density relative to enlarged dentate gyri.
- FB-Pten KOs exhibited increased vessel area and elevated VegfA levels, with preserved vessel density.
- Focal loss of Tsc2 in cortical neurons resulted in a localized increase in vessel density.
Conclusions:
- Hypervascularization is not a universal outcome of mTOR hyperactivation models.
- Loss of Pten and Tsc2 leads to distinct alterations in brain angiogenesis.
- These findings highlight the differential roles of mTOR pathway regulators in vascular development.
