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1 Department of Molecular Physiology and Biophysics, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: gko{at}virginia.edu.
Platelet-Derived Growth Factor (PDGF)-BB, a potent mitogen for mesenchymal cells, also down- regulates the expression of multiple smooth muscle (SM) specific markers. However, there is conflicting evidence whether PDGF-BB represses SM marker expression at a transcriptional or posttranscriptional level, and little is known regarding the mechanisms responsible for these effects. Results of the present studies provide clear evidence that PDGF-BB treatment strongly repressed SM 
-actin, SM MHC and SM22 promoters in SMCs. Of major significance for resolving previous controversies in the field, we found that PDGF-BB-induced repression of SMC marker gene promoters occurred in sub-confluent but
not post-confluent cultures. Of interest, treatment of post-confluent SMCs with a tyrosine phosphatase
inhibitor restored PDGF-BB-induced repression whereas treatment of sub-confluent SMCs with a tyrosine kinase blocker abolished PDGF-BB-induced repression, suggesting that a tyrosine phosphorylation event mediates cell-density dependent effects. Based on previous observations that Ets-1 transcription factor is up-regulated within phenotypically modulated neointimal SMCs, we tested if Ets-1 would repress SM marker expression. Consistent with this hypothesis, results of co-transfection experiments indicated that Ets-1 over-expression reduced the transcriptional activity of SM marker promoter constructs in SMCs whereas it increased activity of SM -actin promoter in endothelial cells. PDGF BB treatment increased expression of Ets-1 in cultured SMC and SM -actin mRNA expression was reduced in multiple independent clones of SMCs stably transfected with an Ets-1 over-expressing construct. Taken together, the results of these experiments provide novel insights regarding possible mechanisms whereby PDGF-BB and Ets-1 may contribute to SMC phenotypic switching associated with
vascular injury.
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