Abstract

Indirect evidence suggests that stimulation of α1-adrenergic receptors (ARs) increases smooth muscle cell (SMC) growth in the growing and adult artery and worsens atherosclerosis and restenosis after balloon injury. In support of a direct adrenergic effect, we have previously shown that α1D-AR stimulation induces SMC hypertrophy in cell and vessel organ culture. Because interactions between α1-ARs and peptide growth factors may be important in normal and pathological SMC growth, herein we examined regulation of α1D-AR expression by growth factors. Platelet-derived growth factor (PDGF)-BB dose- and time-dependently lowered α1D mRNA in cultured quiescent SMCs (e.g., 58% inhibition at 20 ng/ml, 24 h, p < .05), whereas other α1-AR transcripts were unaffected. This same selective effect was seen in the medial layer of aorta in ex vivo organ culture. However, PDGF-AA, insulin-like growth factor-1, insulin, epidermal growth factor, endothelin, histamine, and serotonin had no effect, whereas thrombin induced a modest (1.8-fold) increase. PDGF-BB inhibition of α1D-AR mRNA was accompanied by a 42% reduction in total α1-AR density (p < .05) and a functional decrease in norepinephrine-mediated protein synthesis. α1D mRNA half-life was not significantly affected by PDGF-BB (3.8 versus 3.2 h). However, transcriptional activity of the α1D promoter was inhibited. Reduction in α1D-AR mRNA depended partly on new protein synthesis, and was abolished by protein kinase C inhibition, whereas phosphatidylinositol 3 kinase and mitogen-activated protein kinase kinase inhibition had no effect. These data demonstrate that PDGF-β receptor stimulation (because PDGF-AA had no effect) induces a selective inhibition of α1D-AR expression and hence norepinephrine-mediated SMC growth. This down-regulation may lessen additive or synergistic growth effects of catecholamines with other growth factors in vascular hypertrophic diseases.