Submitted on February 16, 2008
Revised on November 3, 2008
Accepted on November 20, 2008
PDGF-DD, a Novel Mediator of Smooth Muscle Cell Phenotypic Modulation, is Upregulated in Endothelial Cells Exposed to Atherosclerotic-Prone Flow Patterns
James Alexander Thomas1, Rebecca Anne Deaton1, Nicole E Hastings1, Yueting Shang, Christopher W Moehle, Ulf J. Eriksson2, Stavros Topouzis, Brian R Wamhoff3, Brett R Blackman1, and Gary K Owens1*
1 University of Virginia
2 University of Uppsala
3 University of Missouri
* To whom correspondence should be addressed. E-mail: gko{at}virginia.edu.
Platelet-Derived Growth Factor-BB (PDGF-BB) is a well-known smooth muscle cell (SMC) phenotypic modulator that signals by binding to platelet-derived growth factor-
(PDGF-), -
and - membrane receptors. Platelet-Derived Growth Factor-DD (PDGF-DD) is a recently-identified PDGF family member but its role in SMC phenotypic modulation is unknown. Here we demonstrate that PDGF-DD inhibited the expression of multiple SMC genes including SM -actin and SMMHC and upregulated the expression of the potent SMC differentiation repressor gene Kruppel-Like Factor-4 (KLF-4) at both the mRNA and protein levels. Based on the results of promoter reporter assays, changes in SMC gene expression were mediated, at least in part, at the level of transcription. The SMC phenotypic modulatory activity of PDGF-DD was attenuated by pharmacological inhibitors of ERK phosphorylation and by an siRNA to KLF-4, highlighting the role of these two pathways in this process. PDGF-DD failed to repress SM -actin and SMMHC in mouse SMCs lacking a functional PDGF- receptor. Importantly, PDGF-DD was increased within neointimal lesions within the aortic arch region of ApoE-/- mice. Furthermore, human endothelial cells (ECs) exposed to an atherosclerosis-prone flow pattern, as occurs in vascular regions susceptible to the development of atherosclerosis, exhibited a significant increase in expression of PDGF-DD. 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.
