Mechanisms of vascular growth-promoting effects of neuropeptide Y: role of its inducible receptors.
We have previously reported that neuropeptide Y (NPY), a sympathetic cotransmitter and vasoconstrictor, is mitogenic for vascular smooth muscle cells (VSMCs), and now report on the mechanisms mediating these effects. In rat aortic A10 cell line, NPY's potency was greater than that of norepinephrine, and efficacy similar to that of platelet-derived growth factor, but less than that of the full serum, in stimulating cell proliferation; this effect was optimal in cell 60-80% cell density. At lower cell density and serum content, NPY stimulated DNA fragmentation/apoptosis. In rat aortic primary VSMCs (RASMCs), mitogenic effect of NPY was bimodal with the first peak at 1 pM, a decline at 1 nM, and a second peak at 10-100 nM; peptide YY had similar but less efficacious effects. The first NPY's peak was mimicked by Y2 agonists, and blocked by Y2 antagonist (T4-[NPY(33-36]4), and the second mimicked by Y1 agonist and partially blocked by Y1 antagonist, BIBP3226, suggesting a multireceptor mode of action. In A10 and in RASMCs, the expression of NPY receptors, Y1, Y2 and Y5, using RT-PCR was undetectable in quiescent cells but detected after pre-treatment with NPY. The receptor induction was NPY dose-dependent and also affected by incubation time and presence of serum. The NPY mitogenic effects were attenuated by calcium channel blockers, particularly verapamil. In primary cultures of rat coronary endothelial cells (where NPY is also mitogenic), NPY stimulated mitogen-activated protein kinase (MAPK) activity. Thus, the growth-promoting effects of NPY in vascular cells occur at concentrations lower than vasoconstrictive, and appear to be mediated by inducible Y1, Y2, and Y5 receptors, calcium entry and possibly MAPK activation.
Zukowska-Grojec
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Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC, USA. zzukow01@medlib.georgetown.edu
Karwatowska-Prokopczuk
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Fisher
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Ji
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D009478:Neuropeptide Y / Q000494:pharmacology* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000145:classification / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D002121:Calcium Channel Blockers; D017931:DNA Primers; D008934:Mitogens; D009478:Neuropeptide Y; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium