Platelet-derived growth factor inhibits alpha1D-adrenergic receptor expression in vascular smooth muscle cells in vitro and ex vivo.
Indirect evidence suggests that stimulation of alpha1-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 alpha1D-AR stimulation induces SMC hypertrophy in cell and vessel organ culture. Because interactions between alpha1-ARs and peptide growth factors may be important in normal and pathological SMC growth, herein we examined regulation of alpha1D-AR expression by growth factors. Platelet-derived growth factor (PDGF)-BB dose- and time-dependently lowered alpha1D mRNA in cultured quiescent SMCs (e.g., 58% inhibition at 20 ng/ml, 24 h, p <.05), whereas other alpha1-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 alpha1D-AR mRNA was accompanied by a 42% reduction in total alpha1-AR density (p <.05) and a functional decrease in norepinephrine-mediated protein synthesis. alpha1D mRNA half-life was not significantly affected by PDGF-BB (3.8 versus 3.2 h). However, transcriptional activity of the alpha1D promoter was inhibited. Reduction in alpha1D-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-beta receptor stimulation (because PDGF-AA had no effect) induces a selective inhibition of alpha1D-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.
Xin
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Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545, USA.
Yang
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N
Faber
J E
JE
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D000077214:Becaplermin; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006207:Half-Life; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D009924:Organ Culture Techniques; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D009638:Norepinephrine