Document Detail


α2-macroglobulin enhances vasculogenesis/angiogenesis of mouse embryonic stem cells by stimulation of nitric oxide generation and induction of fibroblast growth factor-2 expression.
MedLine Citation:
PMID:  23379699     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
α2-macroglobulin (α2M) is an acute phase protein released upon challenges like cardiac hypertrophy and infarction. α2M signals via lipoprotein LDL receptor related protein (LRP-1) and may induce stem cell activation. In the present study, the effects of α2M on vasculogenesis/angiogenesis and underlying signalling cascades were investigated in mouse embryonic stem (ES) cells. LRP-1 was expressed in ES cells and upregulated during differentiation. α2M dose-dependent increased CD31-positive vascular structures in ES cell-derived embryoid bodies, the early cardiovascular markers isl-1, Nkx-2.5 and flk-1 as well as numbers of VE-cadherin and flk-1 positive cells, but downregulated α-smooth muscle actin. Enhancement of vasculogenesis/angiogenesis by α2M was abolished by the LRP-1 antagonist receptor associated protein (RAP) and LRP-1 blocking antibody. Notably, α2M stimulated vascular growth in the chicken chorioallantois membrane (CAM) assay but not in a human umbilical vein endothelial cell (HUVEC) spheroid model. α2M increased fibroblast growth factor-2 (FGF-2) protein expression which was abolished by RAP, induced nitric oxide (NO) generation as determined by DAF-2DA microfluorometry and activated nitric oxide synthase-3 (NOS-3) as well as extracellular regulated kinase 1,2 (ERK1/2) and phosphatidyl inositol 3-kinase (PI3K). NO generation, the increase in FGF-2 expression and the stimulation of vasculogenesis/angiogenesis by α2M were blunted by the NO-synthase inhibitor L-NAME, the ERK1/2 inhibitor PD98059, and the PI3K inhibitor LY294002. Furthermore vasculogenesis/angiogenesis by α2M was inhibited in presence of the FGF-receptor 1 (FGFR1) antagonist SU5402. In conclusion, α2M stimulates endothelial and early cardiac, but not smooth muscle differentiation of ES cells through generation of NO, activation of ERK1/2 as well as PI3K and induction of FGF-2 expression.
Authors:
Heinrich Sauer; Febina Ravindran; Matthias Beldoch; Fatemeh Sharifpanah; Jamila Jedelská; Bodo Strehlow; Maria Wartenberg
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-2-5
Journal Detail:
Title:  Stem cells and development     Volume:  -     ISSN:  1557-8534     ISO Abbreviation:  Stem Cells Dev.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-2-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197107     Medline TA:  Stem Cells Dev     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Justus Liebig University Giessen, Physiology, Aulweg 126, Giessen, Germany, 35392, 0049-641-9947333, 0049-641-9947219; heinrich.sauer@physiologie.med.uni-giessen.de.
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