Mitogenic actions of neuropeptide Y in vascular smooth muscle cells:: synergetic interactions with the β-adrenergic system

Neuropeptide Y (NPY), a sympathetic cotransmitter and vasoconstrictor, also stimulates vascular smooth muscle cell (VSMC) growth, but which of its Y-1-Y-5 receptors are involved remains unclear. In quiescent rat VSMCs, NPY receptor mRNAs were undetectable (reverse transcription - polymerase chain reaction), but Y-1, Y-2, and Y-5 expression were upregulated or induced following NPY treatment. Concomitantly, NPY increased up to twofold [H-3]thymidine incorporation and cell number bimodally, with a high-affinity peak at pM and low affinity peak at nM concentrations. The Y-1 or Y-5 (not Y-2) 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 Y-1 cDNA transfection restored their mitogenic response (blocked by the Y-1 antagonist). In VSMCs with low or no NPY responsiveness, pre-exposure to beta-adrenergic receptor agonist (isoproterenol), forskolin, or dibu tyryl cAMP augmented NPY's mitogenic effect, while upregulating Y-1, Y-2, and Y-5 receptor expression (isoproterenol only). Thus, NPY is a potent vascular mitogen acting via Y-1 and Y-5 receptors. However, since their expression is low in nonproliferating cells, amplification of NPY's mitogenic responses requires upregulation of at least the Y-1 receptor by NPY itself or beta-adrenergic, cAMP-dependent activation.