title: Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes.
abstract: Aberrant neovascularization supports nutrients and the oxygen microenvironment in tumour growth, invasion and metastasis. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of vascular conditions. Sulforaphane (SFN), an isothiocyanate, has been reported to possess chemopreventive properties. In the present study, the effects of SFN on cell proliferation and tubular formation have been investigated using endothelial cells (ECs) and pericytes in coculture. SFN showed a dose-dependent inhibition on the growth of ECs and pericytes with IC50 values 46.7 and 32.4 µM, respectively. SFN (5-20 µM) inhibited tube formation in a 3D coculture although a lower dose (1.25 µM) promoted 30% more endothelial tube formation than control. Moreover, SFN affected intercellular communication between ECs and pericytes via inhibition of angiogenic factor such as vascular endothelial growth factor (VEGF) expression in pericytes. However, the expression of its receptor (VEGFR-2) was found significantly increased in ECs. These effects were associated with downregulation of prolyl hydroxylase domain-containing protein 1 and 2 (PHD1/2) and activation of hypoxia-inducible factor-1 (HIF) pathway by SFN. Furthermore, thioredoxin reductase-1 was also upregulated by SFN treatment, suggesting that anti-oxidant and redox regulation are involved in angiogenesis. Taken together, the results of the present study suggest that SFN differentially regulates endothelial cells and pericytes disrupting their interplay through the VEGF-VEGFR signalling pathway. Anti-angiogenesis property of SFN indicates that it has potential role as an anticancer agent.
authors.affiliation: The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yichong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, Norfolk NR4 7UQ, UK.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, Norfolk NR4 7UQ, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, Norfolk NR4 7UQ, UK.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Bao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D020286:Pericytes / Q000166:cytology*; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D017879:Isothiocyanates; D013454:Sulfoxides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C016766:sulforaphane