Smooth Muscle Cells and Myofibroblasts Employ Distinct Transcriptional Mechanisms for Smooth Muscle a-Actin Expression

Gan, Qiong, Department of Molecular Physiology and Biological Physics, University of Virginia
Owens, Gary, Department of Molecular Physiology and Biological Physics, University of Virginia

There has been considerable controversy regarding the lineage relationship between smooth muscle cells (SMCs) and myofibroblasts, since both these cell types express common cell-selective markers such as smooth muscle α-actin (SM α-actin). Both SMCs and myofibroblasts play an integral role in injury-repair processes in a wide range of human diseases involving cardiovascular abnormalities. Examples include vein graft remodeling, atherosclerosis, and myocardial remodeling that accompanies renovascular hypertension, tissue fibrosis, and tumor formation. Within the tunica media of normal vessels, the major function of vascular SMCs is to provide tension and structural support. Although myofibroblasts appear within normal tissues where certain mechanical tension is needed, such as in the alveoli, they are mainly activated under pathological conditions when tissue reparation and contraction are required. However, the origins and identities of SMCs and myofibroblasts within these diseases are elusive and complicated because these cells exhibit variable functions including force production, secretion of inflammatory cytokines, and multiple phenotypes. Paradoxically, most investigators use the same marker gene, SM α-actin to identify both myofibroblasts and SMCs in their studies. Although the exact functions of these two cell types within disease states are still unknown, it is critical to distinguish these two cell types to elucidate their roles and introduce cell-specific prophylaxis and treatment. Of major interest, we previously showed that two highly conserved MCAT elements within the SM α-actin promoterIX conferred differential activity in cultured SMCs versus cultured myofibroblasts in that mutation of MCAT elements decreased SM α-actin promoter activity in myofibroblasts whereas the same mutation has no effect on SM α-actin promoter activity in SMCs. These results suggest that there are cell-selective mechanisms that regulate SM α-actin gene transcription. The major focus of this thesis project was to determine the role of MCAT elements within the SM α-actin promoter in vivo in SMCs versus myofibroblasts. Before describing the thesis project in detail, I will review what is known about the identification of SMCs and myofibroblasts, as well as what is known about SM α-actin transcriptional regulation, and provide a summary of our current understanding of MCAT element and transcriptional enhancer factor-1 (TEF-1)-dependent gene transcription.

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PHD (Doctor of Philosophy)
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