Local DIO2 Elevation Is an Adaption in Malformed Cerebrovasculature

Area of Science:

• Vascular Biology
• Endocrinology
• Neurology

Background:

• Cerebrovascular malformations cause significant hemorrhage and neurological deficits.
• Effective treatments for these conditions are currently lacking.
• The role of thyroid hormones (THs) in cerebrovascular malformations is not well understood.

Purpose of the Study:

• To investigate the involvement of iodothyronine deiodinase 2 (DIO2) and TH signaling in cerebrovascular malformations.
• To explore the therapeutic potential of targeting TH signaling for cerebrovascular disorders.

Main Methods:

• Single-cell transcriptome analysis of human cerebral cavernous malformations and brain arteriovenous malformations.
• In vivo studies using mouse models with endothelial-specific knockout of Pdcd10 or Kras mutations.
• Manipulation of Dio2 expression and TH levels (using triiodothyronine or methimazole) in mouse models.

Main Results:

• DIO2 expression and TH signaling were activated in human and mouse cerebrovascular malformations.
• Triiodothyronine replenishment reduced hemorrhage, ECM remodeling, and vascular leakage in mouse models.
• DIO2 silencing or TH inhibition worsened vascular anomalies.
• FOXK1 transcription factor regulates DIO2 via PI3K-Akt-mTOR signaling.
• Triiodothyronine treatment improved mitochondrial function and reduced oxidative stress in a Pgc1a-dependent manner.

Conclusions:

• A novel DIO2-mediated adaptive mechanism exists in malformed cerebrovasculature.
• Targeting TH signaling presents a promising therapeutic strategy for cerebrovascular disorders.