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Cell and Tissue Research

, Volume 358, Issue 2, pp 443–452 | Cite as

β-adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling

  • Fatemeh Sharifpanah
  • Fatjon Saliu
  • Mohamed M. Bekhite
  • Maria Wartenberg
  • Heinrich Sauer
Regular Article

Abstract

The β-adrenoceptor antagonist Propranolol has been successfully used to treat infantile hemangioma. However, its mechanism of action is so far unknown. The hypothesis of this research was that β-adrenoceptor antagonists may interfere with endothelial cell differentiation of stem cells. Specifically, the effects of the non-specific β-adrenergic receptor (β-adrenoceptor) antagonist Propranolol, the β1-adrenoceptor-specific antagonist Atenolol and the β2-adrenoceptor-specific antagonist ICI118,551 on vasculogenesis of mouse embryonic stem (ES) cells were investigated. All three β-blockers dose-dependently downregulated formation of capillary structures in ES cell-derived embryoid bodies and decreased the expression of the vascular cell markers CD31 and VE-cadherin. Furthermore, β-blockers downregulated the expression of fibroblast growth factor-2 (FGF-2), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor 165 (VEGF165), VEGF receptor 2 (VEGF-R2) and phospho VEGF-R2, as well as neuropilin 1 (NRP1) and plexin-B1 which are essential modulators of embryonic angiogenesis with additional roles in vessel remodelling and arteriogenesis. Under conditions of β-adrenoceptor inhibition, the endogenous generation of nitric oxide (NO) as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) was decreased in embryoid bodies, whereas an increase in NO generation was observed with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Consequently, vasculogenesis of ES cells was restored upon treatment of differentiating ES cells with β-adrenoceptor antagonists in the presence of NO donor. In summary, our data suggest that β-blockers impair vasculogenesis of ES cells by interfering with NO generation which could be the explanation for their anti-angiogenic effects in infantile hemangioma.

Keywords

Infantile hemangioma Stem cells Nitric oxide β-adrenergic receptor β-blocker 

Notes

Acknowledgments

This work was supported by the Excellence Cluster Cardiopulmonary System (ECCPS) of the German Research Foundation (DFG) and the International Graduate College GRK1566.

Conflict of Interest Statement

Nothing to declare

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Fatemeh Sharifpanah
    • 1
  • Fatjon Saliu
    • 1
  • Mohamed M. Bekhite
    • 2
    • 3
  • Maria Wartenberg
    • 2
  • Heinrich Sauer
    • 1
  1. 1.Department of PhysiologyJustus Liebig University GiessenGießenGermany
  2. 2.Department of Internal Medicine I, Cardiology DivisionFriedrich Schiller University JenaJenaGermany
  3. 3.Department of Zoology, Faculty of ScienceTanta UniversityTantaEgypt

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