Abstract
BackgroundPlatelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated.ResultsExpression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation.ConclusionsThese findings provide the first systems-level analysis of the PDGF-regulated transcriptome and proteome in normal smooth muscle cells. The analyses revealed an extensive cohort of PDGF-dependent biological processes and connected key transcriptional effectors to their regulation, significantly expanding current knowledge of PDGF-stimulated signaling cascades. These observations also implicate MYC as a novel target for pharmacological intervention in fibroproliferative expansion of smooth muscle, and potentially in cancers in which PDGFR-dependent signaling or MYC activation promote tumor progression.
Highlights
Smooth muscle-rich hollow organs such as the vasculature, airways, gut and urinary tract undergo tissue remodeling following injury
Gene expression regulated by PDGF In order to interrogate global responses to Platelet-derived growth factor-BB (PDGF-BB) at both gene and protein levels, we used primary human bladder smooth muscle cells to perform RNA expression profiling in concert with quantitative analysis of the entire proteome using the SILAC method
Differentially Expressed Gene (DEG) were grouped into clusters (Clusters 1 to 7), based on time-dependent differential expression patterns, by hierarchical cluster analysis
Summary
Smooth muscle-rich hollow organs such as the vasculature, airways, gut and urinary tract undergo tissue remodeling following injury. These alterations in tissue structure include cellular hypertrophy and hyperplasia, increased synthesis and secretion of extracellular matrix, dedifferentiation of smooth muscle cells (SMC) and progressive loss of normal contractile function. Neither the molecular basis of the PDGFR signaling repertoire, nor the extent to which specific elements within these cascades could be exploited for therapeutic benefit has been fully elucidated. Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. Neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated
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