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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015555-02
Application #
6502119
Study Section
Special Emphasis Panel (ZRR1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
City
Portland
State
ME
Country
United States
Zip Code
04102
Soley, Luna; Falank, Carolyne; Reagan, Michaela R (2017) MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells. Curr Osteoporos Rep 15:162-170
Young, K; Krebs, L T; Tweedie, E et al. (2016) Endoglin is required in Pax3-derived cells for embryonic blood vessel formation. Dev Biol 409:95-105
Ames, Jacquelyn J; Contois, Liangru; Caron, Jennifer M et al. (2016) Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway. J Biol Chem 291:2731-50
Contois, Liangru W; Akalu, Abebe; Caron, Jennifer M et al. (2015) Inhibition of tumor-associated ?v?3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 18:31-46
Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E et al. (2013) Altered thermogenesis and impaired bone remodeling in Misty mice. J Bone Miner Res 28:1885-97
Apra, Caroline; Richard, Laurence; Coulpier, Fanny et al. (2012) Cthrc1 is a negative regulator of myelination in Schwann cells. Glia 60:393-403
Contois, Liangru W; Nugent, Desiree P; Caron, Jennifer M et al. (2012) Insulin-like growth factor binding protein-4 differentially inhibits growth factor-induced angiogenesis. J Biol Chem 287:1779-89
Urs, Sumithra; Henderson, Terry; Le, Phuong et al. (2012) Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction. Br J Nutr 108:1025-33
Sathyanarayana, Pradeep; Dev, Arvind; Pradeep, Anamika et al. (2012) Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2. Blood 119:5522-31
Motyl, Katherine J; Dick-de-Paula, Ingrid; Maloney, Ann E et al. (2012) Trabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain. Bone 50:490-8

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