Christopher Chaftari

Background:  Arteriovenous malformations (AVM) are characterized by an abnormal connection between an artery and a vein, bypassing a capillary bed; this leads to a high velocity, low resistance flow which may cause serious complications like stroke, brain abscess and hemorrhage.^1,2,3 Current treatment options include surgical interventions aimed to manage associated risks; however, surgery is not an option for inoperable Grade 6 AVMs.^1,4 Limited knowledge of AVM development has resulted in few FDA-approved therapeutic treatments.⁵ Due to vascular endothelial growth factor (VEGF)’s role in new vessel formation and maturation, several anti-VEGF therapies have been identified as potential AVM treatment options.¹ The purpose of this research is to evaluate the effectiveness of two anti-VEGF therapies: bevacizumab and miR-18a.

Methods:  The PubMed database search was performed using “arteriovenous malformations”, “AVM pathology”, and “AVM treatment” as search terms and included publication dates from January 2018 to February 2023.^1-9

Results:  To evaluate the effect of VEGF on endothelial cells (EC) and mural cells (MC), mouse ECs were embedded in a fibrin matrix and exposed to a PBS or 50 ng/mL VEGF condition for 12 hours and 5 days; QT-PCR was performed.⁶ AVM-ECs obtained from flt-deficient mouse secreted increased VEGF levels and had increased expression of pro-angiogenic genes; this suggests that increased VEGF levels may contribute to AVM pathology.⁶ One proposed AVM therapy is treatment with bevacizumab, a monoclonal VEGF antibody, to decrease VEGF levels and help stabilize AVM vasculature.⁷ In a single arm study with two patients with large unresectable AVMs, patients received bevacizumab 5 mg/kg every 2 weeks for 12 weeks; MRI was performed 26 and 52 weeks post-treatment to measure AVM volume. Bevacizumab treatment decreased occurrence of AVM-associated symptoms but did not decrease AVM volume.⁷ Furthermore, Notch signaling plays an important role in regulating pericyte function and deficiency in Notch signaling was hypothesized to lead to AVM pathology.⁸ To evaluate the effect of Notch signaling on pericyte migration, retinal tissue of WT and Rbpj-deficient mice were compared by eye enucleation at P5, P10, P14, and 6 weeks; immunostaining of retina was performed.⁸ Retinal vasculature of Rbpj-deficient mice had reduced pericyte coverage, which caused impaired vascular remodeling and endothelial barrier function and is in agreement with the proposed role of Notch signaling in pericyte migration.^8,9 The efficacy of miR-18a was evaluated by treatment of human AVM-EC with scrambled miRNA or miR-18a for 24 hours; PCR and co-immunoprecipitation/ELISA were performed.⁴ MiR-18a treatment of AVM-ECs blocked the BMP4/ALK1/ALK2/ALK5 pathways which reduced PAI-1, VEGF, and ultimately Notch signaling levels.⁴ No change was found in BMP9 signaling levels, which is a signaling pathway involved in pericyte migration.⁴ Thus, MiR-18a treatment has the potential stabilize AVM vasculature by lowering overall VEGF levels while having minimal effect on pericyte migration.

Conclusion:  Interventions aimed at lowering overall VEGF levels and its downstream effectors without affecting pericyte migration have the potential to stabilize and improve the morbidity of AVM vasculature. Additional research should be performed to evaluate the dose-dependent effect of bevacizumab on AVM volume and MC migration, and to confirm that in vitro results of miR-18a treatment can be replicated in in vivo and human models.

Works Cited:

1. Schimmel K, Ali MK, Tan SY, et al. Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment. Int J Mol Sci. 2021;22(16):9037. Published 2021 Aug 21. doi:10.3390/ijms22169037
2. Robert F, Desroches-Castan A, Bailly S, Dupuis-Girod S, Feige JJ. Future treatments for hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2020;15(1):4. Published 2020 Jan 7. doi:10.1186/s13023-019-1281-4
3. Sicuri GM, Galante N, Stefini R. Brain Arteriovenous Malformations Classifications: A Surgical Point of View. In: Esposito G, Regli L, Cenzato M, Kaku Y, Tanaka M, Tsukahara T, eds. Trends in Cerebrovascular Surgery and Interventions. Cham (CH): Springer; May 11, 2021.101-106.
4. Marín-Ramos NI, Thein TZ, Ghaghada KB, Chen TC, Giannotta SL, Hofman FM. miR-18a Inhibits BMP4 and HIF-1α Normalizing Brain Arteriovenous Malformations. Circ Res. 2020;127(9):e210-e231. doi:10.1161/CIRCRESAHA.119.316317
5. Rutledge C, Cooke DL, Hetts SW, Abla AA. Brain arteriovenous malformations. Handb Clin Neurol. 2021;176:171-178. doi:10.1016/B978-0-444-64034-5.00020-1
6. Darden J, Payne LB, Zhao H, Chappell JC. Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation. Angiogenesis. 2019;22(1):167-183. doi:10.1007/s10456-018-9648-z
7. Muster R, Ko N, Smith W, et al. Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation. BMJ Neurol Open. 2021;3(1):e000114. Published 2021 Mar 17. doi:10.1136/bmjno-2020-000114
8. Nadeem T, Bogue W, Bigit B, Cuervo H. Deficiency of Notch signaling in pericytes results in arteriovenous malformations. JCI Insigh 2020;5(21):e125940. Published 2020 Nov 5. doi:10.1172/jci.insight.125940
9. Orlich MM, Diéguez-Hurtado R, Muehlfriedel R, et al. Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow. Circ Res. 2022;131(4):308-327. doi:10.1161/CIRCRESAHA.122.321109