Brain arteriovenous malformation biology relevant to hemorrhage and implication for therapeutic development

Abstract

Brain arteriovenous malformations cause intracranial hemorrhage. Molecular characterization of lesional tissue implicates angiogenic (vascular endothelial growth factor, ANG-2, matrix metalloproteinase-9) and inflammatory (cytokines and chemokines) pathways, but the pathogenesis remain obscure and medical therapy is lacking. Macrophage and neutrophil invasion has also been observed in the absence of prior intracranial hemorrhage. Common polymorphisms in interleukin-1beta and activin receptor-like kinase-1 are associated with arteriovenous malformation susceptibility, and polymorphisms in interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and APOE are associated with arteriovenous malformation rupture. These observations suggest that even without a complete understanding of the determinants of arteriovenous malformation development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Furthermore, biomarkers can be established for assessing intracranial hemorrhage risk. Finally, these data will aid in development of model systems for mechanistic testing by development of surrogate phenotypes (microvascular dysplasia) and/or models recapitulating the clinical syndrome of recurrent spontaneous intracranial hemorrhage.

Figure 1. AVM pathogenesis: speculative synthesis of observations

After an inciting event, inflammatory or angiogenic activity (MMP, VEGF) initiates microvascular growth and remodeling, which are stabilized through interplay of pathways including TIE-2/ANG and TGF-β or BMP-9 signaling through the ALK-1/ENG pathway. Lack of Integrin β8 and Hox A5, an anti-angiogenic transcription factor, may also play a role. Normal vessels stabilize, but an incipient AVM undergoes a dysplastic response. Arteriovenous (A-V) shunting and high flow rates synergize with the dysplastic response and with inflammatory signals, causing a vicious cycle in a localized area destined to become the nidus. Eventually, the human disease phenotype emerges. Genetic variation can influence any step of the cycle.