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Brain & Heart DIO2 in malformed cerebrovasculature

coactivator 1-alpha (Pgc1a), a transcriptional coactivator Conflict of interest
of peroxisome proliferator-activated receptor gamma and a
master regulator of mitochondrial biogenesis. This, in turn, Yong Cao is an Editorial Board Member of this journal,
upregulated the expression of key antioxidant enzymes, but was not in any way involved in the editorial and
including superoxide dismutase 2 (Sod2), peroxiredoxin 3 peer-review process conducted for this paper, directly or
(Prdx3), and glutathione peroxidase (Gpx1). The resulting indirectly. Separately, other authors declared that they
cascade effectively reduced reactive oxygen species have no known competing financial interests or personal
accumulation, alleviated mitochondrial dysfunction, relationships that could have influenced the work reported
and suppressed inflammatory infiltration. Crucially, in this paper.
the vascular protective effects of T3 were shown to be Author contributions
dependent on PGC-1α, underscoring its central role in the
TH-mediated reparative pathway. Beyond cerebrovascular Conceptualization: All authors
malformations, THs have been extensively studied in Writing – original draft: All authors
cardiovascular diseases, where they regulate myocardial Writing – review & editing: All authors
function, vascular tone, and endothelial homeostasis. Low
T3 syndrome, often observed in chronic heart failure or Ethics approval and consent to participate
critical illness, is linked to adverse cardiac remodeling, Not applicable.
reduced contractility, and increased mortality, mediated
by both genomic and nongenomic effects. Conversely, T3 Consent for publication
11
supplementation has been shown to improve endothelial Not applicable.
function, reduce vascular stiffness, and protect against
atherosclerosis, partly through the PGC-1α-dependent Availability of data
mitochondrial biogenesis and antioxidant pathways.
10
These findings mirror the mechanisms elucidated in Not applicable.
cerebral vasculature, suggesting that TH-mediated References
vascular repair may be a conserved strategy across different
vascular beds. 1. Li R, Tang Y, Wang H, et al. Local DIO2 elevation is an
adaption in malformed cerebrovasculature. Circ Res.
3. Conclusion 2025;163:1010-1027.
Li et al. identified the localized upregulation of DIO2–T3– doi: 10.1161/circresaha.124.325857
1
PGC-1α–SOD2/PRDX3/GPX1 signaling cascade as an 2. Hong T, Yan Y, Li J, et al. High prevalence of KRAS/BRAF
adaptive mechanism that supported vascular stabilization somatic mutations in brain and spinal cord arteriovenous
in malformed cerebral vessels. This work positions TH malformations. Brain. 2019;142(1):23-34.
activation as a crucial component of an endogenous doi: 10.1093/brain/awy307
cerebrovascular repair mechanism and establishes the 3. Hong T, Xiao X, Ren J, et al. Somatic MAP3K3 and PIK3CA
broader concept of hormonal microenvironmental control mutations in sporadic cerebral and spinal cord cavernous
as a key determinant of disease progression. Rather than malformations. Brain. 2021;144(9):2648-2658.
viewing pathological tissue as irreversibly damaged, this
research encourages us to search for and activate the doi: 10.1093/brain/awab117
dormant reparative mechanisms already embedded in the 4. Lawton MT, Rutledge WC, Kim H, et al. Brain arteriovenous
human body. malformations. Nat Rev Dis Primers. 2015;1:15008.
doi: 10.1038/nrdp.2015.8
Acknowledgments
5. Snellings DA, Hong CC, Ren AA, et al. Cerebral cavernous
None. malformation: From mechanism to therapy. Circ Res.
2021;129(1):195-215.
Funding
doi: 10.1161/circresaha.121.318174
This study is funded by the NSFC General 6. He Q, Huo R, Sun Y, et al. Cerebral vascular malformations:
Program (82171267), the Genomics Platform Pathogenesis and therapy. MedComm (2020).
Construction for Chinese Major Brain Disease-AVM 2024;5(12):e70027.
(PXM2019_026280_000002-AVM), and the Beijing
Advanced Innovation Center for Big Data-based Precision doi: 10.1002/mco2.70027
Medicine (PXM2020_014226_000066). 7. Xu H, Yang Y, Zhou Q, et al. Map3k3 I441M knock-in

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