Background— Secretoneurin is an abundant neuropeptide of the central, peripheral, and autonomic nervous systems, located in nerve fibers characterized by a close interaction with blood vessels and known to stimulate endothelial cell migration.

Methods and Results— We hypothesized that secretoneurin might act as an angiogenic cytokine and tested for these effects in vivo using a mouse cornea neovascularization model and in vitro by assessing capillary tube formation in a matrigel assay. In vivo, secretoneurin-induced neovasculature is characterized by a distinct pattern of arterial and venous vessels of large diameter and length. Immunohistochemical staining for CD-31 revealed endothelial lining of the inner surface of these vessels, and recruitment of α-smooth muscle actin–positive perivascular cells suggests vessel maturation. In vitro, secretoneurin-induced capillary tube formation was dose dependent and specific, confirming that effects of secretoneurin occur directly on endothelial cells. Secretoneurin also stimulated proliferation and exerted antiapoptotic effects on endothelial cells and activated intracellular phosphatidylinositol 3′ kinase/Akt and mitogen-activated protein kinase pathways, as demonstrated by increased phosphorylation of Akt and extracellular signal–regulated kinase.

Conclusions— These data show that secretoneurin represents a novel direct angiogenic cytokine and reiterate the coordinated relationship between nervous and vascular systems.