RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations

BACKGROUND: The blood flow rate of brain arteriovenous malformations (bAVMs) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVMs. However, the underlying molecular properties remain unclear. To identify potential key molecules, signaling pathways, and vascular cell types involved, we compared gene expression profiles between bAVMs with high flow rates and low flow rates (LFR) and validated the functions of selected key molecules in vitro. METHODS AND RESULTS: We performed RNA‐sequencing analysis on 51 samples, including 14 high flow rate bAVMs and 37 LFR bAVMs. Functional pathway analysis was performed to identify potential signals influencing the flow rate phenotype of bAVMs. Candidate genes were investigated in bAVM specimens by immunohistochemical staining. Migration, tube formation, and proliferation assays were used to test the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells and human brain vascular smooth muscle cells. We identified 250 upregulated and 118 downregulated genes in LFR bAVMs compared with high flow rate bAVMs. Wnt signaling was activated in the LFR group via upregulation of FZD10 and MYOC. Immunohistochemical staining showed that vascular endothelial and smooth muscle cells of LFR bAVMs exhibited increased FZD10 and MYOC expression. Experimentally elevating these genes promoted human umbilical vein endothelial cells and migration and tube formation by activating canonical Wnt signaling in vitro. CONCLUSIONS: Our results suggest that canonical Wnt signaling mediated by FZD10 and MYOC is activated in vascular endothelial and smooth muscle cells in LFR bAVMs.