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Brain & Heart DIO2 in malformed cerebrovasculature

cavernous malformation (CCM) and brain arteriovenous Importantly, THs, including thyroxine (T4) and its
malformations (AVMs) are two common cerebrovascular active form triiodothyronine (T3), are evolutionarily
malformations characterized by enlarged and irregular conserved regulators involved in various physiological
structures of small vessels and direct anastomosis between processes, including normal vascular development and
the arterial and venous channels without capillary brain homeostasis. TH also displays therapeutic and repair
intervention, respectively. 4,5 potential in multiple disorders. It improves endothelial
10
Over the past decades, substantial progress has function and lipidemic profiles in atherosclerosis and
been made in elucidating the genetic underpinnings of exhibits anti-inflammatory, anti-apoptotic, and antifibrotic
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CCMs and AVMs. Familial CCMs have been linked effects, contributing to cardioprotection. TH can also
4,5
to heterozygous loss-of-function mutations in either protect the brain from injury by limiting damage and
KRIT1, CCM2, or PDCD10. Recent studies have also promoting recovery. In addition, several case reports point
5
identified somatic mutations in MAP3K3 and PIK3CA to a potential association between TH insufficiency and
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as key drivers of sporadic CCMs. 3,6,7 In brain and spinal vascular malformation. Fukunaga et al. observed that the
cord AVMs, a high prevalence (87.1%) of KRAS/BRAF resolution of underlying hypothyroidism resulted in the
somatic mutations was identified. Endothelial gain of cessation of gastrointestinal bleeding in patients diagnosed
2
KRAS function has been shown to induce brain AVM with small intestinal vascular malformations. Comi
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phenotypes dependent on the mitogen-activated protein et al. reported that two out of 83 children with Sturge–
kinase kinase signaling but not the phosphoinositide Weber syndrome (2.4%), a rare disorder with vascular
3-kinase signaling. 8 malformations in the brain, were diagnosed with central
hypothyroidism, a prevalence much higher than in the
Despite these genetic insights, relatively little is known general population.
about the brain’s intrinsic reparative mechanisms following
malformation development. The capacity for endogenous However, the reparative role of TH in cerebrovascular
repair and adaptation may critically determine the stability malformations remained unexplored until the current
1
or progression of vascular lesions. Enhancing these study by Li et al., which provides the first direct evidence
adaptive responses could mitigate structural anomalies and supporting the therapeutic potential of TH signaling in this
1
reduce the risk of hemorrhage. Furthermore, the current context. The localized overexpression of DIO2 and systemic
key treatments for CCMs and AVMs are neurosurgical T3 supplementation improved endothelial barrier integrity,
intervention and removal or ablation of a symptomatic reduced hemorrhagic burden, and attenuated extracellular
lesion. Nevertheless, these interventions are invasive, matrix remodeling in murine models of CCMs and AVMs.
4,5
expensive, and often contraindicated when lesions are These findings offered novel perspectives on bleeding
located in deep brain regions. Thus, there is an urgent interventions and laid the basis for clinical applications
need to develop pharmacological therapies that promote targeting TH in brain vascular diseases.
vascular stabilization and repair, offering safer and more Mitochondrial dysfunction has recently emerged
accessible treatment alternatives. as a critical factor in vascular malformations. Zhang
et al. demonstrated that endothelial deficiency in any
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2. Discussion of the nuclear genes encoding mitochondrial proteins
Fibroblasts, as central mediators of vascular repair, transcription factor A mitochondrial, cytochrome C
are activated to produce and remodel collagen-rich oxidase assembly factor heme A: Farnesyltransferase,
extracellular matrix. Elucidating their molecular or thioredoxin 2 results in impaired retinal vessel
9
characteristics may provide insights into the repair growth and AVMs, revealing a mechanism where
mechanisms in cerebrovascular disorders. The authors mitochondrial dysfunction via activin receptor-like kinase
conducted differential analyses of cerebrovascular 5-SMAD family member 2 signaling induces vascular
fibroblasts from single-cell data of human CCM/brain AVM malformations. Shi et al. identified that disruption in
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samples and control brain tissue samples. Notably, thyroid endothelial mitochondrial preprotein translocase of outer
hormone (TH) signaling was highly activated in lesion mitochondrial membrane 7-Ras-related C3 botulinum
fibroblasts, accompanied by a significant upregulation of toxin substrate 1 signaling impairs angiogenesis and
DIO2 expression. These findings were corroborated by contributes to cerebrovascular network malformations.
immunostaining and western blotting, which confirmed Herein, Li et al. established the relationship between TH
1
elevated iodothyronine deiodinase 2 (DIO2) expression and cerebrovascular malformations via mitochondrial
in fibroblasts from both human CCM/AVM brain sections biology. T3 treatment restored the diminished expression
and Pdcd10 knockout/Kras G12D mice. of peroxisome proliferator-activated receptor gamma

Volume 3 Issue 3 (2025) 2 doi: 10.36922/BH025150018