Get access

Upregulated autocrine vascular endothelial growth factor (VEGF)/VEGF receptor-2 loop prevents apoptosis in haemangioma-derived endothelial cells

Authors

  • Y. Ji,

    1. Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
    Current affiliation:
    1. Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
    Search for more papers by this author
  • S. Chen,

    1. Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
    Current affiliation:
    1. Pediatric Intensive Care Unit, West China Hospital of Sichuan University, Chengdu, China
    Search for more papers by this author
  • K. Li,

    Corresponding author
    1. Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
    Search for more papers by this author
  • X. Xiao,

    1. Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
    Search for more papers by this author
  • T. Xu,

    1. Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
    Search for more papers by this author
  • S. Zheng

    1. Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
    Search for more papers by this author

  • Funding sources This work was supported in part by grants from the National Natural Science Foundation of China (Grant 81071903, 81072069) to K.L., the Key Clinical Discipline of the Ministry of Health (Grant 201043941) to K.L. and the Mingdao Project of Fudan University (Grant MDJH2012021, MDJH2012020) to Y.J. and S.C.
  • Conflicts of interest The authors declare that they have no competing interests. No institution was involved in the analysis of the data interpretation, in writing the article or in the decision to submit the paper for publication.
  • Y.J. and S.C. contributed equally to this work.

Summary

Background

The autocrine vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 loop is required to maintain the transformed phenotype of many tumours, in part, by preventing apoptotic cell death in response to many different stimuli. However, it is unclear whether constitutive VEGF/VEGFR-2 activation in haemangioma-derived endothelial cells (HaemECs) can lead to a general suppression of apoptosis.

Objectives

The objective of this study was to investigate whether the autocrine VEGF loop promotes HaemEC survival via its receptor, VEGFR-2.

Methods

HaemECs and human umbilical vein endothelial cells (HUVECs) were serum-starved for 12–48 h. Cell apoptosis was measured. The potential mechanisms of VEGF/VEGFR-2-induced HaemEC survival were investigated, and the role of the autocrine VEGF/VEGFR-2 loop in preventing propranolol-induced apoptotic HaemEC death was also analysed.

Results

Compared with HUVECs, HaemECs showed increased resistance to apoptosis induced by serum starvation. Upregulated VEGF/VEGFR-2 signalling in HaemECs induced an autocrine signalling loop, which resulted in Akt activation. Furthermore, this activation of Akt was necessary for VEGF/VEGFR-2-induced protection against serum deprivation-induced HaemEC apoptosis. In addition, Bcl-2, which functions as an anti-apoptotic factor and direct downstream target of PI3K/Akt, was decreased by the inhibition of VEGF/VEGFR-2, which led to an increase in caspase-3 activity, caspase-9 activity and HaemEC apoptosis. Moreover, HaemECs acquired greater resistance to propranolol treatment than HUVECs, whereas inhibition of VEGF/VEGFR-2 signalling in HaemECs sensitized these cells to propranolol-induced apoptosis.

Conclusions

Our results demonstrate that upregulation of the autocrine VEGF/VEGFR-2 loop can induce general resistance to apoptotic stimuli in HaemECs.

Get access to the full text of this article

Ancillary