TRIM28 regulates sprouting angiogenesis through VEGFR-DLL4-Notch signaling circuit

[摘要] Sprouting angiogenesis is a highly coordinately process controlled by vascular endothelial growth factor receptor (VEGFR)-Notch signaling. Here we investigated whether Tripartite motif-containing 28 (TRIM28), which is an epigenetic modifier implicated in gene transcription and cell differentiation, is essential to mediate sprouting angiogenesis. We observed that knockdown ofTRIM28ortholog in zebrafish resulted in developmental vascular defect with disorganized and reduced vasculatures. Consistently, TRIM28 knockdown inhibited angiogenic sprouting of cultured endothelial cells (ECs), which exhibited increased mRNA levels of VEGFR1, Delta-like (DLL) 3, and Notch2 but reduced levels of VEGFR2, DLL1, DLL4, Notch1, Notch3, and Notch4.The regulative effects of TRIM28 on these angiogenic factors were partially mediated by hypoxia-inducible factor 1 alpha (HIF-1 alpha) and recombination signal-binding protein for immunoglobulin kappa J region (RBPJ kappa). In vitro DNA-binding assay showed that TRIM28 knockdown increased the association of RBPJ kappa with DNA sequences containing HIF-1 alpha-binding sites. Moreover, the phosphorylation of TRIM28 was controlled by VEGF and Notch1 through a mechanism involving RBPJ kappa-dual-specificity phosphatase (DUSP)-p38 MAPK, indicating a negative feedback mechanism. These findings established TRIM28 as a crucial regulator of VEGFR-Notch signaling circuit through HIF-1 alpha and RBPJ kappa in EC sprouting angiogenesis.

[发布日期] 2020-11-01

[关键词] TIP CELLS;PROTEIN;VEGF;INHIBITION;DLL4;HIF-1-ALPHA;EXPRESSION;DELTA;RBPJ