Vol. 56, Issue 6, 1143-1151, December 1999

Platelet-Derived Growth Factor Inhibits 1D-Adrenergic Receptor Expression in Vascular Smooth Muscle Cells In Vitro and Ex Vivo

Xiaohua Xin, Nengyu Yang, and James E. Faber

Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Indirect evidence suggests that stimulation of 1-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 1D-AR stimulation induces SMC hypertrophy in cell and vessel organ culture. Because interactions between 1-ARs and peptide growth factors may be important in normal and pathological SMC growth, herein we examined regulation of 1D-AR expression by growth factors. Platelet-derived growth factor (PDGF)-BB dose- and time-dependently lowered 1D mRNA in cultured quiescent SMCs (e.g., 58% inhibition at 20 ng/ml, 24 h, p < .05), whereas other 1-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 1D-AR mRNA was accompanied by a 42% reduction in total 1-AR density (p < .05) and a functional decrease in norepinephrine-mediated protein synthesis. 1D mRNA half-life was not significantly affected by PDGF-BB (3.8 versus 3.2 h). However, transcriptional activity of the 1D promoter was inhibited. Reduction in 1D-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- receptor stimulation (because PDGF-AA had no effect) induces a selective inhibition of 1D-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.