Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells

Circ Res. 2018 Feb 16;122(4):591-605. doi: 10.1161/CIRCRESAHA.117.311950. Epub 2018 Jan 3.

Abstract

Rationale: Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that YAP (Yes-associated protein) plays an important role in regulating the angiogenic activity of ECs.

Objective: The objective of this study was to specify the effect of EC YAP on angiogenesis and its underlying mechanisms.

Method and results: In ECs, vascular endothelial growth factor reduced YAP phosphorylation time and dose dependently and increased its nuclear accumulation. Using Tie2Cre-mediated YAP transgenic mice, we found that YAP promoted angiogenesis in the postnatal retina and tumor tissues. Mass spectrometry revealed signal transducer and activator of transcription 3 (STAT3) as a potential binding partner of YAP in ECs. Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6-induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1-mediated STAT3 nuclear export without affecting its phosphorylation. Moreover, angiopoietin-2 expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or angiopoietin-2 blockage partly attenuated retinal angiogenesis in Tie2Cre-mediated YAP transgenic mice.

Conclusions: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.

Keywords: STAT3 transcription factor; angiopoietin-2; endothelial cells; vascular endothelial growth factor A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism
  • Animals
  • Cell Cycle Proteins
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic*
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Retinal Vessels / growth & development
  • Retinal Vessels / metabolism
  • STAT3 Transcription Factor / metabolism
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiopoietin-2
  • Cell Cycle Proteins
  • Phosphoproteins
  • STAT3 Transcription Factor
  • YAP-Signaling Proteins
  • Yap1 protein, mouse