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

Yinfang Wang, Angom Ramcharan Singh, Yuanyuan Zhao, Tao Du, Yitong Huang, Xiaohong Wan, Debabrata Mukhopadhyay, Ying Wang, Nanping Wang, Peng Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

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 of TRIM28 ortholog 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 α (HIF-1α) and recombination signal-binding protein for immunoglobulin kappa J region (RBPJκ). In vitro DNA-binding assay showed that TRIM28 knockdown increased the association of RBPJκ with DNA sequences containing HIF-1α-binding sites. Moreover, the phosphorylation of TRIM28 was controlled by VEGF and Notch1 through a mechanism involving RBPJκ-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-1α and RBPJκ in EC sprouting angiogenesis.

Original languageEnglish (US)
Pages (from-to)14710-14724
Number of pages15
JournalFASEB Journal
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2020

Keywords

  • DLL4
  • sprouting angiogenesis
  • Tip cell
  • TRIM28
  • VEGFR

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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