Our study now provides evidence that in vivo and in vitro the number of VPC is reduced in conditions of type 2 diabetes and that one major signalling pathway involved is the activation of the transcription factors ETS1 and ETS2. The ETS protein family is a group of transcription factors that share a DNA-binding ETS domain and regulate the expression of a variety of genes including key ones involved in regulation of cell proliferation, differentiation and survival. Because of their critical role in basic cellular processes, dysregulation of ETS transcription factors can be found in many human diseases with the need for neovascularisation, such as cancer. ETS transcription factors have been implicated in the regulation of genes involved in homeostasis, vascular development and angiogenesis, even though no endothelial specific ETS transcription factor has been identified by now. We could clearly show that ETS dysregulation by high levels of glucose leads to impairment of progenitor cell number as well as functional capacity. Apoptozole KDR + cells in the peripheral blood, has recently been shown as these cells predict the outcome in CAD-patients. Although the transcription factor ETS reduces VPC numbers, ETS activity is clearly important in adult angiogenesis. In the resting endothelium, ETS1 is expressed at a very low level. During angiogenesis, re-endothelialisation after balloon denudation in a rat model as well as in scratch wound migration assays, ETS1 is transiently expressed at high levels in endothelial cells, suggesting that during the process of vessel formation or repair upregulation of ETS1 transcription factor expression is required in mature endothelial cells. However, the process of preexisting mature endothelial cells to perform angiogenesis differs completely from VPC-induced vasculogenesis or vascular repair of the damaged endothelial layer. Even though our findings demonstrate the importance of ETS1 in angiogenesis, ETS1 deficient mice develop normally except for an increased perinatal mortality. Especially no vascular phenotype can be detected. Therefore, we hypothesized that most likely other ETS transcription factors can compensate for its loss. Alternatively, these mice might have increased numbers and improved functionality of their endothelial progenitor cells for compensation. Members of the ETS gene family are known to be expressed in the hematopoietic tissue and some of them play a pivotal role in hematopoietic cell development. The special importance of ETS1 regulation in differentiation of Importazole hematopoietic stem cells has previously been shown. During erythroid differentiation, ETS1 is downregulated and exported out of the nucleus. In contrast, during megakaryopoiesis, ETS1 increases and remains in the nucleus. Similarly, it seems that ETS1 activation is required for angiogenesis by sprouting of mature endothelial cells and down-regulation of ETS DNA binding activity is required for increased VPC differentiation from their progenitors as shown in this study. We clearly showed that glucose upregulates ETS DNA binding activity and thereby reduces VPC numbers. In addition, it has been shown that other pro-inflammatory stimuli/cardiovascular risk factors such as TNFa up-regulate ETS transcription factors and reduce the number of endothelial progenitor cells. Therefore, it is tempting to speculate that not only high glucose but also TNFa prevents endothelial cell lineage commitment by ETS transcriptions factor activation.