Molecular Cardiology The Angiogenic Factor Secretoneurin Induces Coronary Angiogenesis in a Model of Myocardial Infarction by Stimulation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells

Background—Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. Methods and Results—In vivo 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 extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (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 heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein. Conclusions—Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease. Key Words: angiogenesis Ⅲ gene therapy Ⅲ myocardial infarction C ongestive heart failure represents an increasing global health problem that occurs predominantly as a result of coronary artery disease. 1 Cardiac dysfunction after myocar-dial infarction (MI) results from 2 major mechanisms: loss of cardiac myocytes in the area of infarction and remodeling of the spared myocardium in the left ventricle (LV). Inadequate structural adaptation of the vascular bed in the area of cardiac myocyte hypertrophy accounts for the progression of LV dysfunction of the heart. Although ischemia induces endog-enous myocardial angiogenesis, vascular growth is insufficient to maintain normal capillary density in the hypertro-phied myocardium. Induction of neovascularization is recognized to be a valid approach to modify the pathological changes of ventricular remodeling. Gene transfer of growth factors known to induce angiogenesis such as vascular endothelial …