FLK1 (VEGFR2), a receptor tyrosine kinase, is a critical component for blood cell and vessel formation as evidenced by knockout studies. FLK1 continues to play an important role in postnatal and pathological angiogenesis. Therefore, understanding molecular mechanisms of Flk1 expression is essential for delineating the pathways involved in vessel formation as well as postnatal angiogenesis. We have demonstrated that the transcription factor ER71 (also known as ETV2) is a critical regulator of FLK1 and thereby it is essential for generation of vascular endothelial cells. Deficiency in Er71 leads to embryonic lethality with a complete absence of vascular structures and blood cells. We also showed that ER71 functions to directly regulate Flk1, indicating the important role of the ER71-FLK1 axis in pathophysiological angiogenesis. However, the mechanisms by which ER71 regulates Flk1 expression and neovascularization remain largely unexplored. Our preliminary studies provide compelling evidence showing its potent and unexpected functions in the mechanism of vascular endothelial cell generation and revascularization in the adult. With our new data, we hypothesize that the interaction between ER71 and OVOL2 is essential for optimal FLK1+ cell generation and revascularization. Additionally, we will test the hypothesis that ER71 regulates FLK1+ cell generation through miR126-Spread1-MAPK signaling. Finally, we will test the hypothesis that reactivation of ER71 following ischemic injury promotes neovascularization through Flk1 expression and thus activates the VEGF-FLK1 signaling pathway. Upon completed, our findings will provide a new and detailed insight into the role of ER71 in vascular endothelial cell generation and revascularization in the adult, which can lead to the development of new therapeutic strategies for cardiovascular diseases.

Public Health Relevance

The transcription factor ER71 (also known as ETV2) is a critical regulator of FLK1 whose function is essential for vessel development and post-natal angiogenesis. The overall goal of this proposal is to investigate mechanisms by which ER71 regulates Flk1 expression and neovascularization by employing mouse genetic models and mouse embryonic stem cell differentiation system. Our preliminary studies provide compelling evidence showing its potent and unexpected functions in the mechanism of vascular endothelial cell generation and revascularization in the adult, and thus outcome from this application will provide a new research platform which could lead to the development of new therapeutic strategies for cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119291-04
Application #
9099864
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2013-08-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lee, Sangho; Park, Changwon; Han, Ji Woong et al. (2017) Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. Circ Res 120:848-861
Park, Changwon; Lee, Tae-Jin; Bhang, Suk Ho et al. (2016) Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol 36:86-96
Oh, Se-Yeong; Kim, Ju Young; Park, Changwon (2015) The ETS Factor, ETV2: a Master Regulator for Vascular Endothelial Cell Development. Mol Cells 38:1029-36
Toya, Sophie P; Wary, Kishore K; Mittal, Manish et al. (2015) Integrin ?6?1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 33:1719-29
Lee, Shin-Jeong; Park, Changwon; Lee, Ji Yoon et al. (2015) Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair. Sci Rep 5:11019
Liu, Fang; Li, Daofeng; Yu, Yik Yeung Lawrence et al. (2015) Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2. EMBO Rep 16:654-69
Kim, Ju Young; Lee, Ra Ham; Kim, Tae Min et al. (2014) OVOL2 is a critical regulator of ER71/ETV2 in generating FLK1+, hematopoietic, and endothelial cells from embryonic stem cells. Blood 124:2948-52