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- Document type:
- Journal Article; Research Support, Non-U.S. Gov't
- Author(s):
- Mannell, H; Hellwig, N; Gloe, T; Plank, C; Sohn, HY; Groesser, L; Walzog, B; Pohl, U; Krötz, F
- Title:
- Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo.
- Abstract:
- Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitroas well as new vessel growth ex vivo(p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction (p < 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis (annexin V staining, p < 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n = 3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth.
- Journal title abbreviation:
- J Vasc Res
- Year:
- 2008
- Journal volume:
- 45
- Journal issue:
- 2
- Pages contribution:
- 153-63
- Language:
- eng
- Fulltext / DOI:
- doi:10.1159/000110081
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/17962719
- Print-ISSN:
- 1018-1172
- TUM Institution:
- Institut für Experimentelle Onkologie und Therapieforschung
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