Platelet-derived growth factor inhibits alpha 1D-adrenergic receptor expression in vascular smooth muscle cells in vitro and ex vivo

Indirect evidence suggests that stimulation of alpha 1-adrenergic receptors (ARs) increases smooth muscle cell (SMC) growth in the growing and adult a rtery and worsens atherosclerosis and restenosis after balloon injury. In s upport of a direct adrenergic effect, we have previously shown that alpha 1 D-AR stimulation induces SMC hypertrophy in cell and vessel organ culture. Because interactions between alpha 1-ARs and peptide growth factors may be important in normal and pathological SMC growth, herein we examined regulat ion of alpha 1D-AR expression by growth factors. Platelet-derived growth fa ctor (PDGF)-BB dose- and time-dependently lowered alpha 1D mRNA in cultured quiescent SMCs (e.g., 58% inhibition at 20 ng/ml, 24 h, p < .05), whereas other alpha 1-AR transcripts were unaffected. This same selective effect wa s seen in the medial layer of aorta in ex vivo organ culture. However, PDGF -AA, insulin-like growth factor- 1, insulin, epidermal growth factor, endot helin, histamine, and serotonin had no effect, whereas thrombin induced a m odest (1.8-fold) increase. PDGF-BB inhibition of alpha 1D-AR mRNA was accom panied by a 42% reduction in total alpha 1-AR density (p < .05) and a funct ional decrease in norepinephrine-mediated protein synthesis. alpha 1D mRNA half-life was not significantly affected by PDGF-BB (3.8 versus 3.2 h). How ever, transcriptional activity of the alpha 1D promoter was inhibited. Redu ction in alpha 1D-AR mRNA depended partly on new protein synthesis, and was abolished by protein kinase C inhibition, whereas phosphatidylinositol 3 k inase and mitogen-activated protein kinase kinase inhibition had no effect. These data demonstrate that PDGF-beta receptor stimulation (because PDGF-A A had no effect) induces a selective inhibition of alpha 1D-AR expression a nd hence norepinephrine-mediated SMC growth. This down-regulation may lesse n additive or synergistic growth effects of catecholamines with other growt h factors in vascular hypertrophic diseases.