The insulin-like growth factor binding protein 2 (IGFBP2) has been implicated in the regulation of insulin-like growth factor 1 (IGF1) activity in most tissue and organs. IGFBP2 has, however, also been reported to have additional intrinsic, IGF independent properties. For example, high levels of IGFBP2 are linked to increased tumour angiogenesis in humans. In this setting increased angiogenesis has been suggested to be caused by indirect rather than direct modulation of endothelial cells.Hypothesis
Using in vitro and in vivo models of angiogenesis, Here we tested the hypothesis that IGFBP2 is able to modulate endothelial cell function directly. using in vitro and in vivo models of angiogenesis.Results and conclusions
Treatment of human umbilical vein endothelial cells (HUVEC) with 15 nM human IGFBP2 resulted in the activation of the MAPK pathway and the Akt/PKB pathway within 15 min of stimulation in immunoblotting experiments. Treatment of HUVEC with 15 nM IGFBP2 for 72 hour increased the number of subcellular protrusions in a three dimensional culture assay. Mice globally overexpressing human IGFBP2 showed increased activation of the MAPK pathway in the aorta when compared to wild type (WT) littermate controls as determined by immunoblotting. When compared to WT micelittermate controls, global overexpression of human IGFBP2 in vivo resulted in increased tip cell formation in the postnatal retina, corresponding to our results from the in vitro sprouting assay. Further analysis of these mice revealed an increase in the vascular density and the number of branch points but not total vessel outgrowth in comparison to littermate controls. Our data suggests IGFBP2 is able to directly modulate endothelial cell function thus positively regulating angiogenesis in vitro and in vivo.