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Advanced Neurology Targets and medications for AVM of CNS

be able to stabilize the vasculature of AVMs, but it has been treatments will likely continue to be the sole management
reported that patients under MMP inhibition treatment still strategy for AVMs for a considerable amount of time, and
carry a risk for BAVM rupture. The use of thalidomide, on the lack of pharmacotherapy for brain and spinal AVMs
the other hand, may enhance the integrity of AVM vessels represents an unmet clinical need and, without a doubt, a
and reduce the hemorrhagic risk, but its noticeable toxicities significant potential for innovative research.
undoubtedly restrict its use. In a patient with Cobb syndrome,
trametinib has shown to be effective for the treatment of Acknowledgments
extracranial AVMs but not spinal cord AVMs, indicating None.
that AVMs of the CNS may not be sensitive to trametinib,
just as the natural course of brain and spinal AVMs is Funding
more stable than that of extracranial AVMs. The safety of None.
trametinib should also be assessed for patients without
malignant diseases. Although some of the findings have not Conflict of interest
been fully translated into clinical studies, they are still of
interest. The Notch signaling pathway has been the subject The authors declare that they have no competing interests.
of a number of research, some of which have revealed that it Author contributions
is activated in surgical specimens and its upregulation alters
the vascular structure, as shown in a mouse model of Notch- Conceptualization: Zhengsong Li, Jiaxing Yu, and Tao
mediated AVMs [68,69] . The previous studies have also shown Hong
that members of the Notch signaling pathway and their Supervision: Tao Hong and Hongqi Zhang
downstream molecules are associated with angiogenesis [70,71] Writing – original draft: Zhengsong Li, Yueshan Feng, Shiju
and that hypoxia upregulates Notch signaling, thus causing Zhang, Yuan Zhou, and Jiaxing Yu
inflammation and vascular remodeling [72,73] , whose Writing – review & editing: Zhengsong Li
subsequent reactions are related to the formation of AVM.
Notch is associated with multiple pathways of conduction Ethics approval and consent to participate
but its mechanism in AVM has not been fully elucidated [74,75] . Not applicable.
The study of Notch inhibitors is challenging due to their
wide range of interactions. Unfortunately, clinical studies Consent for publication
are not yet in sight. As of now, we know that Notch inhibitor Not applicable.
causes dose-dependent inhibition of endothelial cell
migration and network formation in vitro . A Smad family Availability of data
[76]
member 4 (Smad4)-inducible, endothelial cell-specific
knockout (Smad4-iECKO) mouse model has established Not applicable.
that angiopoietin-2 inhibition rescues AVM formation, References
which is indeed an inspiring finding .
[77]
1. Leblanc GG, Golanov E, Awad IA, et al., 2009, Biology of
We speculate that the relatively stable natural vascular malformations of the brain NINDS workshop
course of CNS AVMs compared to that of malignant collaborators. Biology of vascular malformations of the
tumors presents a challenge in the development of brain. Stroke, 40(12): 694-702.
pharmacotherapy for AVMs. The evidence on the growth https://doi.org/10.1161/STROKEAHA.109.563692
of AVMs in the brain or spinal cord is anecdotal, and
the existence of arteriovenous shunts with expanded 2. Gomes MM, Bernatz PE, 1970, Arteriovenous fistulas:
vascular caliber mainly relies on arterial blood flow A review and ten-year experience at the Mayo clinic. Mayo
Clin Proc, 45(2): 81-102.
rather than aberrant signaling pathways, as is the case
with neoplasms. Therefore, pharmacotherapy strategies 3. Eerola I, Boon LM, Mulliken JB, et al., 2003, Capillary
for malignant tumors may not be appropriate for AVMs. malformation-arteriovenous malformation, a new clinical
Given the applicability of the genetic-based mouse model and genetic disorder caused by RASA1 mutations. Am J
of sporadic AVMs, we believe that further studies should Hum Genet, 73(6): 1240-1249.
be devoted to assessing the difference in expression https://doi.org/10.1086/379793
between malformed vessels and intact vasculature. The 4. Gallione CJ, Repetto GM, Legius E, et al., 2004, A
development of specific markers may help distinguish combined syndrome of juvenile polyposis and hereditary
AVM vessels from normal vessels, which may facilitate haemorrhagic telangiectasia associated with mutations in
precise delivery of drugs for AVMs. In conclusion, invasive MADH4 (SMAD4). Lancet, 363(9412): 852-859.

Volume 1 Issue 3 (2022) 7 https://doi.org/10.36922/an.v1i3.211