RT Journal Article
SR Electronic
T1 Platelet-Derived Growth Factor Inhibits α1D-Adrenergic Receptor Expression in Vascular Smooth Muscle Cells In Vitro and Ex Vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1143
OP 1151
DO 10.1124/mol.56.6.1143
VO 56
IS 6
A1 Xiaohua Xin
A1 Nengyu Yang
A1 James E. Faber
YR 1999
UL http://molpharm.aspetjournals.org/content/56/6/1143.abstract
AB 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.