Angiogenesis plays an essential role during normal growth and development and is also an important requirement for the growth of essentially all tumors. Therefore a better understanding of this process will be beneficial both to basic science as well as in the clinic. Drugs that inhibit angiogenesis have been shown to be effective at limiting the growth of tumors, and there are also many clinical applications where the ability to promote angiogenesis would be beneficial. These efforts have focused on the angiogenic factors themselves with much less known about their intracellular mediators. The goals of this project is to better understand the transcriptional regulation of angiogenesis, focusing on endothelial cell differentiation and the regulation of the activity of the MEF2 transcription factor. Recently, it was reported that the phenotype of mice lacking MEF2C died because of vascular defects. In these mice, endothelial cells seemed to differentiate fairly normally and express endothelial-specific genes, however they did not undergo the process of tubulogenesis. We have recently found a similar requirement for MEF2 activity in the terminal phases of skeletal myogenesis. In proliferating myoblasts MEF2 is present, but in a transcriptionally inactive or weakly active form. As differentiation proceeds MEF2 protein expression increases and becomes activated allowing terminal differentiation to occur. This activation of MEF2 is negatively regulated by the transcription factor Twist. Interestingly, Twist is also expressed in angioblasts and endothelial cells, and mice that are deficient in the Twist gene die because of defects in the vasculature. Therefore, Twist expression in endothelial cells may play a similar role as it does in myoblasts by regulating the activity of MEF2. In this proposal we will extend our initial observations in muscle to endothelial cell differentiation. A better understanding of the signaling pathways, transcription factors involved, and the mechanisms of their actions should provide a better insight into the angiogenic process and may furnish new targets to try and modify this process.
The specific aims of this proposal are:
Aim 1) Determine the mechanism by which Twist inhibits MEF2 activity and endothelial cell behavior.
Aim 2) Determine the effect of over-expression of Twist and positive and negative forms of MEF2 during vascular injury and angiogenesis.
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