Secretoneurin (SN) is a highly conserved neuropeptide located in nerve fibers along blood vessels and is upregulated by hypoxia in neuronal and skeletal muscle cells. SN was shown to induce angiogenesis but the precise mode of function remains enigmatic.Methods and Results
In a rat model of myocardial infarction secretoneurin improved left ventricular function, inhibited remodeling and reduced scar formation. In the infarct border zone secretoneurin induced coronary angiogenesis as shown by increased density of capillaries and arteries. In-vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis and activated Akt and ERK in coronary endothelial cells. Effects were abrogated by a VEGF antibody and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells and binding was blocked by heparinase indicating that secretoneurin stimulates binding of VEGF to heparansulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its co-receptor neuropillin-1. In endothelial cells secretoneurin also stimulated FGF receptor-3 and IGF-1 receptor and in coronary vascular smooth muscle cells we observed stimulation of VEGF receptor-1 and FGF receptor-3. Exposure of cardiomyocytes to hypoxia increased secretoneurin m-RNA and protein.Conclusions
Our data show that SN acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low affinity binding sites and neuropillin-1 and stimulates further growth factor receptors like FGF receptor 3 in coronary vascular cells. Our in-vivo findings indicate that SN might be a promising therapeutic tool in ischemic heart disease.