RNF213 Knockdown and Inflammation Promote Angiogenesis and Phenotype Switching by JAK2/STAT3 Pathway in Moyamoya Disease

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease. Ring finger protein 213 (RNF213) is a susceptibility gene for MMD. Numerous studies have highlighted that RNF213 regulates angiogenesis; its precise regulatory role and mechanism remain controversial. Moreover, the impacts and mechanisms of RNF213 on vascular smooth muscle cell (VSMC) phenotype switching are also rarely reported. Inflammation is an important factor in promoting the occurrence and development of MMD, necessitating further investigations to clarify its specific role. In vitro experiments, human brain microvascular endothelial cells (HBMECs), and human aortic smooth muscle cells (HASMCs) were used. RNF213 function was suppressed using small interfering RNA, while inflammatory stimulation was induced by lipopolysaccharide (LPS). We found that knockdown of RNF213 could promote HBMEC proliferation, migration, and angiogenesis and inhibit Apoptosis in HBMECs. Moreover, these effects were enhanced by treating with LPS. Bioinformatics analysis revealed protein interactions between RNF213 and JAK2/STAT3. Subsequent validation demonstrated that loss of RNF213 function and LPS could upregulate the expression of JAK2, STAT3, and VEGF in HBMECs. Inhibition of the JAK2/STAT3 signaling pathway effectively reversed the increase in VEGF expression induced by RNF213 dysfunction. Furthermore, RNF213 dysfunction and LPS treatment could promote the proliferation, migration, and phenotype switching and inhibit Apoptosis in HASMCs. Activation of the JAK2/STAT3 signaling pathway appeared to facilitate the phenotype switching of HASMCs. Impairment of RNF213 function was found to promote angiogenesis and phenotype switching in MMD, with these effects being enhanced under inflammatory conditions, potentially mediated by the activation of the JAK2/STAT3 signaling pathway.

Angiogenesis; JAK2/STAT3 signaling pathway; Moyamoya disease; Phenotype switching; Ring finger protein 213.