Yes-Associated Protein Promotes Angiogenesis Via Signal Transducer and Activator of Transcription 3 in Endothelial Cells
Rationale: Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that Yes-associated protein (YAP) plays an important role in regulating the angiogenic activity of ECs.
Objective: To specify the effect of EC YAP on angiogenesis and its underlying mechanisms.
Methods 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 (Tie2Cre-YAPTg) 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 (Ang2) expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or Ang2 blockage partly attenuated retinal angiogenesis in Tie2Cre-YAPTgmice.
Conclusions: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of Ang2.
- Received September 10, 2017.
- Revision received December 20, 2017.
- Accepted December 28, 2017.