The Role of Pitx2 in the Control of Smooth Muscle Cell Differentiation during Embryonic Development

II Precise control of differentiation of vascular smooth muscle cells (SMCs) plays a key role in vascular development and pathophysiology, including in diverse vascular diseases, such as atherosclerosis, hypertension and restenosis. However, the mechanisms controlling differentiation of vascular smooth muscle cells (SMCs) are poorly understood. In various cell types, including cardiac, skeletal and smooth muscle cells, the homeodomain family of transcription factors have been demonstrated to play crucial roles in multiple biological processes, including cell proliferation, differentiation and migration. The purpose of this project was to characterize the role of one homeodomain protein, Pitx2 and its function in control of SMC differentiation. We identified the Pitx2 gene as a transcription factor which was rapidly induced in A404 cells, an in vitro cell culture model for studying early stages of SMC differentiation. Over-expression of Pitx2 activated expression of multiple SMC differentiation marker genes, whereas knockout of the Pitx2 gene repressed expression of these genes in vitro. Pitx2 was found to bind to a highly conserved homeodomain binding TAATCC element within the promoter-enhancer region of SMC differentiation marker genes, and cooperatively activated gene transcription through interacting with serum response factor. In addition, Pitx2 induced hyperacetylation of histones on the promoter region of SMC differentiation marker genes through modulating III the exchange of histone deacetylases and histone acetyltransferases. Of major significance, mice lacking the Pitx2 gene exhibited impaired induction of multiple SMC differentiation marker genes in great arteries, including dorsal aorta and branchial arch arteries, in early embryonic development stage. Taken together, the results presented in this thesis provide compelling evidence that Pitx2 is a critical transcription factor in regulation of SMC differentiation marker gene expression during embryonic development.

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