Notch activation suppresses endothelial cell migration and sprouting via miR-223-3p targeting Fbxw7

Autor: Ruonan Wang, Ziyan Yang, Liang Liang, Xingxing Feng, Bo Che, Xiaoyan Zhang, Qijun Zheng, Xianchun Yan, Hua Han
Rok vydání: 2022
Předmět:
Zdroj: In Vitro Cellular & Developmental Biology - Animal. 58:124-135
ISSN: 1543-706X
1071-2690
Popis: Angiogenesis involves temporo-spatially coordinated endothelial cell (EC) proliferation, differentiation, migration, and sprouting. Notch signaling is essential in regulating EC behaviors during angiogenesis, but its downstream mechanisms remain incompletely defined. In the current study, we show that miR-223-3p is a downstream molecule of Notch signaling and mediates the role of Notch signaling in regulating EC migration and sprouting. In human umbilical vein endothelial cells (HUVECs), Notch activation by immobilized Dll4, a Notch ligand, upregulated miR-223-3p, and Notch activation-mediated miR-223-3p upregulation could be blocked by a γ-secretase inhibitor (DAPT). miR-223-3p overexpression apparently repressed HUVEC migration, leading to attenuated lumen formation and sprouting capacities. Transcriptome comparison and subsequent qRT-PCR validation further indicated that miR-223-3p downregulated the expression of multiple genes involved in EC migration, axon guidance, extracellular matrix remodeling, and angiogenesis. In addition, miR-223-3p antagonist transfection abolished Notch-mediated repression of EC migration and sprouting. By quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and reporter assay analysis, we confirmed that miR-223-3p directly targeted F-box and WD repeat domain-containing 7 (Fbxw7). Meanwhile, Fbxw7 overexpression could efficiently rescue the impaired migration capacity of ECs under miR-223-3p overexpression. In summary, these results identify that Notch activation-induced miR-223-3p suppresses EC migration and sprouting via Fbxw7.
Databáze: OpenAIRE
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