Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition

Abstract

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).

Keywords: arteriovenous malformations (AVMs); endothelial cells (ECs); endothelial dysfunction; endothelial-to-mesenchymal transition (EndMT).

Figure 1

Schematic overview of the factors related to endothelial dysfunction in bAVM pathogenesis. Germline or EC-specific somatic mutations trigger EC dysfunction, which is influenced by various factors, including other vascular and immune cells, humoral factors such as inflammatory cytokines/chemokines, and hemodynamic flow. The direct or indirect interactions with these factors orchestrate EC dysfunction featured by disturbed polarization and migration, acquiring mesenchymal features, loss of junction proteins, and excessive angiogenesis, leading to abnormal vascular development and remodeling, as well as impairment of vessel integrity, subsequently resulting in brain arteriovenous malformations.

Figure 2

Simplified scheme of signaling pathways in ECs relevant to bAVM pathogenesis. Activation of SMADs in ECs can occur via ligand (BMP9/10, TGFβ) binding to the TGFβ receptor complexes. Loss-of-function mutations on ENG and ALK-1 gene, the co-receptors of TGFβR and BMPR, and SMAD2, are the cause of HHT syndromes. Circulating sENG can act as a decoy receptor for the ligands of BMPs in TGFβ signaling, which is implicated in bAVM development. VEGFR2 binding with VEGF-A activates PI3K/AKT/mTOR signaling, which can be inhibited by PTEN, an effector of TGFβ signaling. The RAS/RAF/MEK/ERK pathway, a straightforward signaling cascade to regulate various cellular functions. RAS can activate PI3K, whereas AKT inhibits RAF. Several activating somatic KRAS mutations were found in human sporadic bAVMs. EGFR binding with EGF can also activate RAS signaling. Activating somatic KRAS mutations detected in human sporadic bAVMs are sufficient to induce bAVMs. RASA1 interacting with EPHB4 is the endogenous inhibitor of RAS, and mutations on the RASA1 gene have been implicated in low-flow AVM formation. Canonical (Dsh-mediated) WNT signaling, non-canonical (Ca²⁺-dependent) WNT signaling, and Notch pathways are also involved in bAVM pathological mechanisms through regulation of EndMT and vascular specifications. Evidence suggest that these pathways cross-communicate with TGFβ signaling. The listed signaling pathways regulate their target gene expression involved in EC functions (cell cycle, survival, proliferation, and migration), EndMT, vessel specification, and angiogenesis. Abnormal activation/suppression of these pathways by germline or somatic mutations is relevant to vascular malformations.

Figure 3

A schematic representation of EndMT involved in bAVMs. The hallmark of EndMT is ECs acquisition of mesenchymal characteristics through diverse molecular signaling, mainly TGFβ signaling. EndMT is a crucial process in vascular development under normal circumstances, by providing ECs as the sources of new vessels and EC mobility; however, EndMT being disrupted by various stimuli (e.g., mutations) contributes to pathologic vessel development, including that of bAVMs. Identification of the exact mechanisms in which bAVM-relevant germline or somatic mutations regulate EndMT and the role of EndMT plays in bAVM pathology will be critical for developing novel therapeutic approaches to treat bAVM patients by targeting of this process.