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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 20, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn258
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

PDGF-BB stimulates vasculogenesis of embryonic stem cell-derived endothelial cells by calcium-mediated generation of reactive oxygen species

Sabine Lange#, Jaqueline Heger#, Gerhild Euler#, Maria Wartenberg§, Hans-Michael Piper# and Heinrich Sauer#

# Department of Physiology, Justus-Liebig-University Giessen, Germany
§ Department of Internal Medicine I, Friedrich-Schiller-University Jena, Germany

Address for Correspondence Prof. Dr. Heinrich Sauer Department of Physiology Justus-Liebig-University Giessen Aulweg 129 35392 Giessen, Germany phone: +49-641-9947333 fax: +49-641-9947219 Email: heinrich.sauer{at}physiologie.med.uni-giessen.de

Aims: Platelet-derived growth factor BB (PDGF-BB) has been assigned a critical role in vascular growth and recruitment of perivascular mural cells. The purpose of the present study was to investigate the signalling events underlying the stimulation of vasculogenesis of mouse embryonic stem (ES) cells by PDGF-BB.

Methods and results: PDGF-BB increased vascular sprouting and branching of capillary-like structures in embryoid bodies as evaluated by computer-assisted analysis of CD31-positive cell structures. It also activated extracellular-regulated kinase 1,2 (ERK1,2) and c-Jun N-terminal kinase (JNK) but not p38 mitogen-activated protein kinase (MAPK) or PI 3-kinase (PI3K). Microfluorometric analysis of fluo-4 fluorescence revealed that treatment with PDGF-BB raised intracellular Ca2+ levels in differentiating ES cells expressing the PDGF receptor β (PDGFR-β), an effect that was abolished in the presence of the intracellular Ca2+ chelator BAPTA. Furthermore, PDGF-BB raised reactive oxygen species (ROS) levels in embryoid bodies as evaluated using the redox-sensitive dye H2DCF-DA. ROS generation was blunted in the presence of the NADPH oxidase inhibitors diphenylen iodonium (DPI) and apocynin as well as in the presence of BAPTA, suggesting that ROS generation is regulated by intracellular Ca2+ transients. The stimulation of vasculogenesis of ES cells upon treatment with PDGF-BB was significantly inhibited by the ERK1,2 inhibitor U0126, the NADPH oxidase inhibitors DPI, apocynin, 4-(2-aminoethyl)benzenesulfonylfluoride (AEBSF) and VAS2870, the free radical scavengers vitamin E and N-(2-mercaptopropionyl)glycin (NMPG) as well as by BAPTA.

Conclusion: Our data demonstrate that the pro-vasculogenic effects of PDGF-BB are mediated by Ca2+-induced ROS generation, resulting in the activation of an ERK1,2-mediated signal transduction cascade.

KEYWORDS embryonic stem cell; angiogenesis; platelet-derived growth factor; reactive oxygen species

Time for primary review: 35 days


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