Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

Abstract

Brain arteriovenous malformations (AVMs) cause intracranial hemorrhage (ICH), especially in young adults. Molecular characterization of lesional tissue provides evidence for involvement of both angiogenic and inflammatory pathways, but the pathogenesis remains obscure and medical therapy is lacking. Abnormal expression patterns have been observed for proteins related to angiogenesis (e.g., vascular endothelial growth factor, angiopoietin-2, matrix metalloproteinase-9), and inflammation (e.g., interleukin-6 [IL-6] and myeloperoxidase). Macrophage and neutrophil invasion have also been observed in the absence of prior ICH. Candidate gene association studies have identified a number of germline variants associated with clinical ICH course and AVM susceptibility. A single nucleotide polymorphism (SNP) in activin receptor-like kinase-1 (ALK-1) is associated with AVM susceptibility, and SNPs in IL-6, tumor necrosis factor-alpha (TNF-alpha), and apolipoprotein-E (APOE) are associated with AVM rupture. These observations suggest that even without a complete understanding of the determinants of AVM development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Further, biomarkers can now be established for assessing ICH risk. These data will generate hypotheses that can be tested mechanistically in model systems, including surrogate phenotypes, such as vascular dysplasia and/or models recapitulating the clinical syndrome of recurrent spontaneous ICH.

Figure 1. Speculative synthesis of experimental observations

relevant to AVM pathogenesis is presented in a simplified, conceptual fashion. After an inciting event or events, inflammatory or angiogenic activity (MMP, VEGF) initiates microvascular growth and remodeling, which are stabilized through interplay of pathways that include TIE-2/ANG and ALK-1 / Endoglin. TGF-β signaling occurs primarily through ALK-5 in smooth muscle and BMP-9 signaling through ALK-1 in the endothelium (see Figure 2). Normal vessels stabilize, but a region that represents an incipient AVM undergoes a dysplastic response. Arteriovenous (A–V) shunting and high flow rates synergize with the dysplastic response and involve classical inflammatory signals, causing a vicious cycle in a localized area destined to become the AVM nidus. Eventually, the human disease phenotype results. Genetic variation can influence any and all of the pathways.

Figure 2. Signaling pathways

Speculative synthesis of signaling pathways. The αvβ8 gene, which has an IL-1β responsive region in human and mouse β8 promoters, is critical to liberate TGF-β from LAP. MMP-9 activity and inflammation are associated with IL-1β, TNF-α and IL-6. TGF-β signaling proceeds through the ALK-5 receptor expressed primarily on vascular smooth muscle. Endothelial cells express primarily ALK-1, which signals via the BMP-9 ligand. The ALK-1 signal is required for EC maturation, which when abrogated, leads to inappropriate EC migration and proliferation. Endoglin is an accessory receptor that can modulate both TGF-β and ALK-1 signaling. ALK-1 and ALK-5 signal via distinct SMAD effector pathways that converge on the common co-effector, SMAD4, in order to effect gene expression.