Our understanding on the cardiovascular system has been widened over the past decades, but still millions of patients with cardiovascular disease (CVD), the most devastating disease in the United States and the rest of the world, await more effective means to treat the disease. Thus, a comprehensive insight into the mechanisms regulating the function of the cardiovascular system is urgently needed. Previously, we have demonstrated an indispensable role of the transcription factor ETV2 (also known as ER71) in cardiovascular system development. Also, our recent studies with genetically modified mice provide compelling evidence that show ETV2?s potent and novel functions in the vascular regeneration in adults. Mice lacking endothelial ETV2 exhibit significantly impaired new vessel formation in response to tissue injuries including laser-induced eye injury, skin wounding, or hindlimb ischemic injury, which are models for age-related macular degeneration, general wound healing, and peripheral arterial disease, respectively. Moreover, a lentiviral delivery of ETV2 into ischemic hindlimbs leads to an improved recovery of blood flow, augments angiogenic gene expression and enhances vascular regeneration, highlighting a requisite postnatal function of ETV2 in an injury-induced neovascularization. However, current knowledge on mechanisms by which ETV2 functions in the cardiovascular system and vascular regeneration is very limited. Our preliminary results suggest that ETV2 directs the expression of endothelial genes and thus generation of cardiovascular lineages by regulating the status of H3K9 methylation though the interaction with KDM4A, a histone demethylase. In addition, our investigations strongly suggest a functional correlation between the NF?B pathway and ETV2 in mediating injury-induced neovascularization. Furthermore, we have several lines of evidence showing that myelomonocyte ETV2 plays a significant role in neovascularization upon ischemic insults. Building upon these strong and novel evidence as well as tools, we will decipher mechanisms and functions of ETV2, 1) by determining the epigenetic regulatory role of the interaction between ETV2 and KDM4A for cardiovascular lineage generation, 2) by investigating the role of the NF?B as a direct upstream regulator of ETV2 in mouse models of hindlimb ischemia and tumor, 3) by revealing the novel functions of myelomonocyte ETV2, contributing to neovascularization by regulating inflammation. The outcome of this work will reveal uncovered functions of ETV2 in vascular development and functions as well as tissue repair, significantly advancing our limited knowledge on vascular biology. Thus, our findings could lead to the development of novel, effective therapeutic strategies for diseases related to dysfunctional vessel formation, an important translational aspect of the proposed studies.

Public Health Relevance

The ETS domain transcription factor ETV2/ER71 has emerged ever since our first report as an essential regulator of cardiovascular system development and plays an important function in vascular regeneration and tissue repair. The overall goal of this proposal is to investigate novel mechanisms of how ETV2 functions and regulates the cardiovascular system and vascular regeneration by bringing together diverse approaches spanning from epigenetics, next generation sequencing, molecular and cellular biology to mouse genetics, mouse ischemia injury and tumor models. Our identification of ETV?2 novel functions will provide an in-depth knowledge and novel opportunities for designing potential treatment options for cardiovascular disease and thus will have a wide- opened impact on improving public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL119291-07
Application #
10129642
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2013-08-01
Project End
2023-06-30
Budget Start
2020-08-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Physiology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
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