PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns.
Platelet-derived growth factor (PDGF)-BB is a well-known smooth muscle (SM) cell (SMC) phenotypic modulator that signals by binding to PDGF alphaalpha-, alphabeta-, and betabeta-membrane receptors. PDGF-DD is a recently identified PDGF family member, and its role in SMC phenotypic modulation is unknown. Here we demonstrate that PDGF-DD inhibited expression of multiple SMC genes, including SM alpha-actin and SM myosin heavy chain, and upregulated expression of the potent SMC differentiation repressor gene Kruppel-like factor-4 at the mRNA and protein levels. On the basis of the results of promoter-reporter assays, changes in SMC gene expression were mediated, at least in part, at the level of transcription. Attenuation of the SMC phenotypic modulatory activity of PDGF-DD by pharmacological inhibitors of ERK phosphorylation and by a small interfering RNA to Kruppel-like factor-4 highlight the role of these two pathways in this process. PDGF-DD failed to repress SM alpha-actin and SM myosin heavy chain in mouse SMCs lacking a functional PDGF beta-receptor. Importantly, PDGF-DD expression was increased in neointimal lesions in the aortic arch region of apolipoprotein C-deficient (ApoE(-/-)) mice. Furthermore, human endothelial cells exposed to an atherosclerosis-prone flow pattern, as in vascular regions susceptible to the development of atherosclerosis, exhibited a significant increase in PDGF-DD expression. These findings demonstrate a novel activity for PDGF-DD in SMC biology and highlight the potential contribution of this molecule to SMC phenotypic modulation in the setting of disturbed blood flow.
Thomas
James A
JA
Department of Molecular Physiology and Biological Physics, Univeresity of Virginia, Charlottesville, VA, USA.
Deaton
Rebecca A
RA
Hastings
Nicole E
NE
Shang
Yueting
Y
Moehle
Christopher W
CW
Eriksson
Ulf
U
Topouzis
Stavros
S
Wamhoff
Brian R
BR
Blackman
Brett R
BR
Owens
Gary K
GK
D000199:Actins / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013997:Time Factors; D015854:Up-Regulation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D000096985:Calponins
D000199:Actins; D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008222:Lymphokines; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018995:Myosin Heavy Chains; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020797:Receptor, Platelet-Derived Growth Factor beta; D011994:Recombinant Proteins; D050807:ets-Domain Protein Elk-1; D000096985:Calponins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; C427493:PDGFD protein, human; C498951:Pdgfd protein, mouse; C498862:Acta2 protein, rat; C051615:transgelin