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RNF213 gene mutations are the cause behind Moyamoya disease, a rare cerebrovascular occlusive disease. However, the function of RNF213 in the vascular system and the impact of its loss of function are not yet comprehended. To understand RNF23 function, we performed gene knockdown (KD) in vascular cells and performed various phenotypical analysis as well as extensive transcriptome and epitranscriptome profiling. Our data revealed that RNF213 KD led to disrupted angiogenesis in HUVEC, in part due to downregulation of DNA replication and proliferation pathways. Furthermore, HUVEC cells became sensitive to LPS induced inflammation after RNF213 KD, leading to retarded cell migration and enhanced macrophage transmigration. This was evident at the level of transcriptome as well. Interestingly, RNF213 led to extensive changes in mRNA splicing that were not previously reported. In vascular smooth muscle cells (vSMCs), RNF213 KD led to alteration in cytoskeletal organization, contractility, and vSMCs function related pathways. Finally, RNF213 KD disrupted endothelial-to-vSMCs communication in co-culture models. Overall, our results indicate that RNF213 KD sensitizes endothelial cells to inflammation, leading to altered angiogenesis. Our results shed the light on the important links between RNF213 mutations and inflammatory/immune inducers of MMD and on the unexplored role of epitranscriptome in MMD.

journal of cerebral blood flow and metabolism

RNF213 loss of function reshapes vascular transcriptome and spliceosome leading to disrupted angiogenesis and aggravated vascular inflammatory responses