A commentary on “Local DIO2 Elevation Is an Adaption in Malformed Cerebrovasculature”

Abstract

This commentary discusses the study “Local DIO2 Elevation Is an Adaption in Malformed Cerebrovasculature.” The authors investigated the role of iodothyronine deiodinase 2 (DIO2), an enzyme that converts thyroxine (T4) to active triiodothyronine (T3), and thyroid hormone (TH) signaling in cerebrovascular malformations. Using single-cell transcriptomic analyses of two prototypical malformations, cerebral cavernous malformations (CCMs) and brain arteriovenous malformations (AVMs), they identified activated TH signaling accompanied by elevated DIO2 expression in fibroblasts isolated from lesion samples. Functionally, supplementation with exogenous DIO2 or T3 effectively reduced brain hemorrhage, excessive extracellular matrix remodeling, and vascular leakage in CCM mouse models (endothelial-specific Pdcd10 knockout mice) and brain AVMs (endothelial-specific Kras^G12D mutant mice). Conversely, genetic silencing of DIO2 or pharmacological inhibition of TH signaling deteriorated vascular anomalies and increased hemorrhagic burden. Mechanistic investigations revealed that elevated DIO2 expression is driven by activation of the fibroblast phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin-forkhead box K1 pathway in malformed vessels. Furthermore, the study elucidated the molecular basis by which T3 ameliorates cerebrovascular pathology: T3 administration suppressed inflammatory infiltration and restored mitochondrial homeostasis by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha-superoxide dismutase 2/peroxiredoxin 3/glutathione peroxidase 1 axis, thereby reducing reactive oxygen species accumulation in malformed brain vessels. Collectively, the authors delineate a novel, localized DIO2-mediated adaptive response in malformed brain vessels and highlight TH signaling as a promising therapeutic target for cerebrovascular disorders.

Keywords

Thyroid hormones / Vascular malformations / Arteriovenous malformation / Cerebral cavernous malformation / Hemorrhage

Acknowledgments

None.

Funding

This study is funded by the NSFC General Program (82171267), the Genomics Platform Construction for Chinese Major Brain Disease-AVM (PXM2019_026280_000002-AVM), and the Beijing Advanced Innovation Center for Big Data-based Precision Medicine (PXM2020_014226_000066).

Conflict of interest

Yong Cao is an Editorial Board Member of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

Author contributions

Conceptualization: All authors

Writing - original draft: All authors

Writing - review & editing: All authors

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

Not applicable.

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