Characterizing the Microenvironment of Cerebral Arteriovenous Malformations to Test Novel Treatment Modalities

TL;DR

This review explores the molecular mechanisms behind brain arteriovenous malformations and how they can lead to new treatments.

Contribution

The paper highlights novel insights into signaling pathways and genetic mutations involved in bAVM formation.

Findings

Dysregulation in VEGF, TGF-β/BMP9/10–ENG–ALK1–SMAD4, Notch, and MAPK/ERK pathways drives abnormal angiogenesis in bAVMs.

KRAS/BRAF/MAPK21 mutations are specifically linked to sporadic bAVMs.

Animal models of bAVMs have validated human genetic profiles and provided new mechanistic insights.

Abstract

Brain arteriovenous malformations (bAVMs) consist of a tangled nidus of abnormal dilated vessels characterized by direct connections between arteries and veins that lack an intervening capillary bed, creating a high-to-low flow pressure system that is predisposed to spontaneous hemorrhage with significant associated neurologic morbidity and mortality. Treatment options for bAVMs include the following: surgical resection, intravascular embolization to obliterate blood flow through the AVM, and radiosurgery. Understanding the molecular mechanisms of bAVM formation and factors that predispose it to hemorrhage can lead to novel treatments that can improve the prognosis for patients. This review summarizes emerging insights into the complex and dynamic molecular mechanisms of bAVMs. Dysregulation in key VEGF, TGF-β/BMP9/10–ENG–ALK1–SMAD4, Notch, and MAPK/ERK signaling pathways drive abnormal angiogenesis in both syndromic and sporadic forms, with KRAS/BRAF/MAPK21 mutations specifically linked to the latter. Advances in bAVM-induced animal models have corroborated many of the genetic profiles found in humans, and they continue to provide novel insights into bAVM mechanisms. Collectively, these mechanistic findings are guiding translational advances, with targeted therapies and liquid biopsy approaches emerging as avenues for precision treatment and improved patient outcomes.

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