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Brain & Heart

COMMENTARY
A commentary on “Local DIO2 Elevation Is an

Adaption in Malformed Cerebrovasculature”

Qiheng He 1,2 and Yong Cao 1,2,3 *
1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
2 Center for Basic and Translational Medicine, China National Clinical Research Center for
Neurological Diseases, Beijing, China
3 Department of Management Office, Beijing Institute of Brain Disorders, Beijing, China

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).
*Corresponding author:
Yong Cao Conversely, genetic silencing of DIO2 or pharmacological inhibition of TH signaling
(caoyong@bjtth.org) deteriorated vascular anomalies and increased hemorrhagic burden. Mechanistic
Citation: He Q, Cao Y. investigations revealed that elevated DIO2 expression is driven by activation of
A commentary on “Local the fibroblast phosphoinositide 3-kinase-protein kinase B-mammalian target of
DIO2 Elevation Is an rapamycin-forkhead box K1 pathway in malformed vessels. Furthermore, the study
Adaption in Malformed
Cerebrovasculature.” Brain & Heart. elucidated the molecular basis by which T3 ameliorates cerebrovascular pathology:
2025;3(3):025150018. T3 administration suppressed inflammatory infiltration and restored mitochondrial
doi: 10.36922/BH025150018 homeostasis by activating the peroxisome proliferator-activated receptor gamma
Received: April 9, 2025 coactivator 1-alpha-superoxide dismutase 2/peroxiredoxin 3/glutathione peroxidase
Revised: June 3, 2025 1 axis, thereby reducing reactive oxygen species accumulation in malformed brain
vessels. Collectively, the authors delineate a novel, localized DIO2-mediated adaptive
Accepted: June 11, 2025
response in malformed brain vessels and highlight TH signaling as a promising
Published online: July 1, 2025 therapeutic target for cerebrovascular disorders.
Copyright: © 2025 Author(s).
This is an Open-Access article
distributed under the terms of the Keywords: Thyroid hormones; Vascular malformations; Arteriovenous malformation;
Creative Commons Attribution Cerebral cavernous malformation; Hemorrhage
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience 1. Introduction
Publishing remains neutral with Cerebrovascular malformations, encompassing a spectrum of structural abnormalities
regard to jurisdictional claims in
published maps and institutional in the cerebrovascular architecture, pose a significant clinical challenge due to
1-3
affiliations. their propensity to cause hemorrhage and neurological impairment. Cerebral

Volume 3 Issue 3 (2025) 1 doi: 10.36922/BH025150018