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Upregulated autocrine vascular endothelial growth factor ( VEGF )/ VEGF receptor‐2 loop prevents apoptosis in haemangioma‐derived endothelial cells
Author(s) -
Ji Y.,
Chen S.,
Li K.,
Xiao X.,
Xu T.,
Zheng S.
Publication year - 2014
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.12592
Subject(s) - autocrine signalling , vascular endothelial growth factor , apoptosis , vascular endothelial growth factor a , downregulation and upregulation , protein kinase b , cancer research , kinase insert domain receptor , biology , paracrine signalling , microbiology and biotechnology , receptor , signal transduction , vegf receptors , biochemistry , gene
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 ( H aem EC s) can lead to a general suppression of apoptosis. Objectives The objective of this study was to investigate whether the autocrine VEGF loop promotes H aem EC survival via its receptor, VEGFR ‐2. Methods Haem EC s and human umbilical vein endothelial cells ( HUVEC s) were serum‐starved for 12–48 h. Cell apoptosis was measured. The potential mechanisms of VEGF / VEGFR ‐2‐induced H aem EC survival were investigated, and the role of the autocrine VEGF / VEGFR ‐2 loop in preventing propranolol‐induced apoptotic H aem EC death was also analysed. Results Compared with HUVEC s, H aem EC s showed increased resistance to apoptosis induced by serum starvation. Upregulated VEGF / VEGFR ‐2 signalling in H aem EC s induced an autocrine signalling loop, which resulted in A kt activation. Furthermore, this activation of A kt was necessary for VEGF / VEGFR ‐2‐induced protection against serum deprivation‐induced H aem EC apoptosis. In addition, B cl‐2, which functions as an anti‐apoptotic factor and direct downstream target of PI 3 K / A kt, was decreased by the inhibition of VEGF / VEGFR ‐2, which led to an increase in caspase‐3 activity, caspase‐9 activity and H aem EC apoptosis. Moreover, H aem EC s acquired greater resistance to propranolol treatment than HUVEC s, whereas inhibition of VEGF / VEGFR ‐2 signalling in H aem EC s 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 H aem EC s.