Mitogenic actions of neuropeptide Y in vascular smooth muscle cells: synergetic interactions with the beta-adrenergic system.
Neuropeptide Y (NPY), a sympathetic cotransmitter and vasoconstrictor, also stimulates vascular smooth muscle cell (VSMC) growth, but which of its Y1-Y5 receptors are involved remains unclear. In quiescent rat VSMCs, NPY receptor mRNAs were undetectable (reverse transcription-polymerase chain reaction), but Y1, Y2, and Y5 expression were upregulated or induced following NPY treatment. Concomitantly, NPY increased up to twofold [3H]thymidine incorporation and cell number bimodally, with a high-affinity peak at pM and low affinity peak at nM concentrations. The Y1 or Y5 (not Y2) antagonist alone did not change the high-affinity peak but decreased the low affinity peak by 50% and fully blocked NPY's response when combined. In VSMCs lacking NPY receptors and responsiveness, transient Y1 cDNA transfection restored their mitogenic response (blocked by the Y1 antagonist). In VSMCs with low or no NPY responsiveness, pre-exposure to beta-adrenergic receptor agonist (isoproterenol), forskolin, or dibutyryl cAMP augmented NPY's mitogenic effect, while upregulating Y1, Y2, and Y5 receptor expression (isoproterenol only). Thus, NPY is a potent vascular mitogen acting via Y1 and Y5 receptors. However, since their expression is low in nonproliferating cells, amplification of NPY's mitogenic responses requires upregulation of at least the Y1 receptor by NPY itself or beta-adrenergic, cAMP-dependent activation.
Pons
Jennifer
J
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20057, USA.
Kitlinska
Joanna
J
Ji
Hong
H
Lee
Edward W
EW
Zukowska
Zofia
Z
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D018076:DNA, Complementary / Q000235:genetics; D004357:Drug Synergism; D006133:Growth Substances / Q000378:metabolism*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018075:RNA, Complementary / Q000187:drug effects / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000235:genetics; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013552:Swine; D013936:Thymidine / Q000378:metabolism; D014162:Transfection
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D018076:DNA, Complementary; D006133:Growth Substances; D009478:Neuropeptide Y; D018075:RNA, Complementary; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D018013:Receptors, Neuropeptide; D017476:Receptors, Neuropeptide Y; D004247:DNA; D000242:Cyclic AMP; D013936:Thymidine