The Src homology-2 domain containing tyrosine phosphatase SHP-2 is activated by the angiogenic growth factor bFGF. It is unknown, however, whether SHP-2 affects bFGF induced angiogenesis. Therefore, we investigated the role of SHP-2 in proliferation, survival and sprouting of human microvascular- and umbilical vein endothelial cells (HMEC, HUVEC) using antisense oligonucleotide (AS-ODN). Knock-down of SHP-2 decreased bFGF dependent endothelial cell proliferation by 55±7% (p<0.05; n=12) as compared to nonsense oligonucleotide (NS-ODN) treatment. Cell cycle analysis by flow cytometric propidium iodide staining (p<0.05, n=6) and subsequent Annexin V staining (p<0.01, n=9) revealed a significantly higher number of apoptotic cells following SHP-2 AS-ODN transfection compared to NS-ODN treatment. Furthermore, inhibition of SHP-2 significantly impaired the formation of capillary like structures in cultured primary endothelial cells as well as new vessel sprouting from mouse aortic rings embedded in Matrigel. SHP-2 knock-down in endothelial cells was further associated with a decreased phosphorylation of the PI3-Kinase (n=3), Akt (n=5) and ERK1/2 (n=5). Our results indicate that SHP-2 promotes endothelial cell survival and proliferation, possibly by bFGF dependent PI3-K and MAP kinase activation, and is necessary for new vessel formation. These observations suggest SHP-2 to be a key enzyme in the control of bFGF induced angiogenesis.