Neuropeptide Y

A Novel Angiogenic Factor From the Sympathetic Nerves and Endothelium

From the Departments of Physiology and Biophysics (Z.Z.-G., E.K.-P., S.M., H.J.), Obstetrics and Gynecology (J.R.), and Cell Biology (Y.Y., W.-T.C.), Georgetown University Medical Center, Washington, DC; Cell Biology Section, National Institute of Dental Research, Bethesda, Md (H.K.K.); Cardeza Foundation for Hematological Research, Jefferson University, Philadelphia, Pa (W.R., D.S.G.); and Department of Hypertension, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (E.G.).

Correspondence to Zofia Zukowska-Grojec, Department of Physiology and Biophysics, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20007. E-mail zzukow01{at}medlib.georgetown.edu

Abstract—Sympathetic nerves have long been suspected of trophic activity, but the nature of their angiogenic factor has not been determined. Neuropeptide Y (NPY), a sympathetic cotransmitter, is the most abundant peptide in the heart and the brain. It is released during nerve activation and ischemia and causes vasoconstriction and smooth muscle cell proliferation. Here we report the first evidence that NPY is angiogenic. At low physiological concentrations, in vitro, it promotes vessel sprouting and adhesion, migration, proliferation, and capillary tube formation by human endothelial cells. In vivo, in a murine angiogenic assay, NPY is angiogenic and is as potent as a basic fibroblast growth factor. The NPY action is specific and is mediated by Y1 and Y2 receptors. The expression of both receptors is upregulated during cell growth; however, Y2 appears to be the main NPY angiogenic receptor. Its upregulation parallels the NPY-induced capillary tube formation on reconstituted basement membrane (Matrigel); the Y2 agonist mimics the tube-forming activity of NPY, whereas the Y2 antagonist blocks it. Endothelium contains not only NPY receptors but also peptide itself, its mRNA, and the "NPY-converting enzyme" dipeptidyl peptidase IV (both protein and mRNA), which terminates the Y1 activity of NPY and cleaves the Tyr¹-Pro² from NPY to form an angiogenic Y2 agonist, NPY_3–36. Endothelium is thus not only the site of action of NPY but also the origin of the autocrine NPY system, which, together with the sympathetic nerves, may be important in angiogenesis during tissue development and repair.

Key Words: angiogenesis • chemotaxis • dipeptidyl peptidase IV • NPY receptor • endothelial cell

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