Both proliferation and apoptosis accompany the vascular remodeling that occurs in hypertension and atherosclerosis. While the sympathetic nerves are known to be trophic, the mitogenic effects of catecholamines are weak. The current hypothesis is that the neuropeptide Y (NPY) co-transmitter in these nerves is the major factor involved in vascular smooth muscle growth. Preliminary data are provided to show that NPY stimulates growth and apoptosis. The receptor subtype and mechanism of action are not yet known.
The aims are to 1) further define the growth effects of NPY and to understand the balance between mitogenic and apoptotic effects; 2) study the regulation of the NPY metabolizing enzymes in association with the growth effects, as a means of understanding whether these enzymes might be involved in regulating the growth versus antigrowth effects; 3) determine the subtypes of receptors and 4) their signaling pathways. Antisense oligos will be used in cell culture to elucidate the pathways linked to each receptor subtype. Evidence for a novel receptor will lead to an effort to clone the new receptor. Finally, 5) studies of the effects of NPY on neointimal proliferation in rat carotid artery will be used to test the hypothesis that injury is associated with up-regulation of the NPY system in the vessel and that treatment with antagonists will reverse these effects. These studies will lead to information useful in developing new anti-mitogenic therapies.
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