mTORC1 Signaling in Brain Endothelial Progenitors Contributes to CCM Pathogenesis.

Area of Science:

• Neuroscience
• Vascular Biology
• Cell Signaling

Background:

• Cerebral cavernous malformations (CCMs) increase stroke and seizure risk.
• CCM development is linked to blood-brain barrier (BBB) integrity loss.
• The precise signaling pathways in brain endothelial cells/progenitors initiating CCMs remain unclear.

Purpose of the Study:

• Investigate the role of CCM3 in brain endothelial cells (ECs) and endothelial progenitor cells (EPCs).
• Elucidate the signaling mechanisms underlying CCM initiation and progression.
• Determine the involvement of mTOR signaling in CCM pathogenesis.

Main Methods:

• Generated brain EC-specific CCM3-deficient (Pdcd10BECKO) mice.
• Utilized single-cell RNA-sequencing to analyze EC and EPC populations.
• Performed in vivo imaging, immunofluorescence, and biochemical assays to study mTOR signaling and Cav1.

Main Results:

• CCM3 deficiency led to decreased BBB-associated ECs but increased mitotic ECs and a unique EPC cluster with high stem cell markers.
• mTOR signaling was upregulated in CCM lesions in both mouse models and human samples.
• Inhibition of mTORC1 (but not mTORC2) signaling prevented CCM formation; rapamycin treatment ameliorated CCM pathogenesis.

Conclusions:

• CCM3 is essential for maintaining blood-brain barrier integrity.
• Loss of CCM3 triggers mTORC1 signaling in brain EPCs, initiating and promoting CCM pathogenesis.
• Targeting mTORC1 signaling represents a potential therapeutic strategy for CCMs.