Question: The tyrosine phosphatase SHP-2 plays an important role in growth factor signalling. We previously demonstrated its importance for growth factor dependent angiogenesis. Here we studied whether SHP-2 influences endothelial cell proliferation, vessel sprouting and HIF-1α signalling upon hypoxia. Methods: Overexpression of wild type (SHP-2 WT), catalytically inactive (SHP-2 CS) or constitutively active (SHP-2 E76A) SHP-2 in human microvascular endothelial cells (HMEC) was achieved by lentiviral transduction. Vessel sprouting was assessed by the aortic ring assay. Cells and isolated aortae were exposed to hypoxia (95 % N2, 5% CO2) for 4h or 24h. Proliferation was assessed by MTT reduction. HIF-1α protein levels and ERK activity (Thr/Tyr-phosphorylation) were detected by western blot. HIF-1α mRNA levels were quantified using real-time PCR. Results: Compared to SHP-2 WT, expression of constitutively active SHP-2 enhanced proliferation during normoxia by 48±8% and hypoxia by 57±10% (both p<0.05, ANOVA, n=8). After hypoxia exposure, vessel sprouting ex vivo (p<0.05, ANOVA, n=5) as well as hypoxia inducible factor 1α (HIF-1α) protein levels (p<0.05, ANOVA, n=4), but not mRNA levels (n=3), were enhanced by 5-fold and 1.3-fold respectively in cells expressing constitutively active SHP-2. This was associated with an enhanced activity of the potential HIF-1α regulator MAPK ERK1/2 (n=3).The increased hypoxic proliferation was completely blocked upon HIF-1α inhibition (Echinomycin 10ng/ml, p<0.05, t-test, n=6) and also upon treatment with a MAPK-pathway inhibitor (GW5074, p<0.05, t-test, n=6). In contrast, expression of catalytically inactive SHP-2 impaired proliferation during normoxia (p<0.05, ANOVA, n=7) and hypoxia (p<0.05, ANOVA, n=8) as well as ex vivo vessel sprouting after hypoxia exposure (p<0.05, n=4) compared to SHP-2 WT. In addition, hypoxic HIF-1α protein accumulation (p<0.05, ANOVA, n=4) and ERK1/2 activity (n=3) were reduced. However, the reduction in HIF-1α protein was rescued by treatment with proteasomal inhibitors (MG132 or Epoximicin, n=3). Conclusion: In addition to being important for angiogenic processes during normoxia, SHP-2 also affects endothelial cell proliferation and vessel sprouting during hypoxic conditions. During hypoxia endothelial cell proliferation and HIF-1α protein stabilisation is further enhanced when increasing SHP-2 catalytic activity, possibly through ERK activation. Thus, controlled induction of SHP-2 catalytic activity may be therapeutically promising for angiogenesis induction in ischemic conditions.