Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

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 vitro as
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. Copyright (C)
2007 S. Karger AG, Basel.