# HEMANGIOBLAST DEVELOPMENT AND REGULATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $724,035

## Abstract

Hemangiogenesis, the formation of functional blood and endothelial cells (EC), is requisite for successful
embryogenesis. We have so far demonstrated that blood and ECs develop from the PDGFRa-FLK1+
hemangiogenic mesoderm, which originates from the PDGFRa+ nascent mesoderm through a
PDGFRa+FLK-1+ intermediary (i.e., PDGFRa+ ® PDGFRa+FLK1+ ® PDGFRa-FLK1+). We recently
performed single-cell RNA sequencing and mapped a developmental pathway of the hemangiogenesis. In
this process, we discovered that hemangiogenic lineage shares a close molecular ontogeny with the
smooth muscle cell (SMC) lineage. Moreover, in vivo, yolk sac SMCs still retained the Flk1+ mesoderm
transcriptome signature. Therefore, we proposed that the SMC lineage is the default pathway of the FLK1+
mesoderm. In further delineating mechanisms involved in the hemangiogenesis, we have shown that the
transition from PDGFRa+FLK1+ to the PDGFRa-FLK1+ stage is dependent on the ETS transcription factor
ETV2, a critical factor for the formation of hematopoietic and endothelial cell lineages. At the molecular
level, ETV2 positively activates genes essential for hematopoietic and endothelial cell lineage specification.
Two critical events occur in the transition from PDGFRa+FLK1+ to the PDGFRa-FLK1+ stage. First, Etv2
expression becomes higher, suggesting an Etv2 threshold mechanism in hemangiogenesis critical for this
transition. Second, ETV2 target gene loci become accessible, suggesting epigenetic and chromatin
changes occurring during this transition. We identified BAF155, a subunit of the mammalian SWI/SNF
chromatin-remodeling BAF (BRG1/BRM associated factor) complex, as a cofactor of ETV2. This finding
suggests that ETV2 utilizes BAF in reconfiguring chromatin accessibility of its target gene loci. A deeper
understanding of the lineage relationship among FLK1+ populations and molecular processes occurring
during the transition from PDGFRa+FLK1+ to PDGFRa-FLK1+ will be critical for further understanding how
the hematopoietic and vascular systems are established in embryogenesis. This proposal's overarching
goal is to gain deeper molecular insights into the regulation of Flk1+ lineage allocation concerning Etv2 and
Baf155 expression and function. To this end, we will determine if hemangiogenic vs. SMC lineage fate of
the FLK1+ mesoderm is controlled by the Etv2 dosage (aim 1), determine if PDGFRa+FLK1+ to the
PDGFRa-FLK1+ transition requires ETV2 mediated Flk1 enhancer switching mechanisms (aim 2), and
determine the chromatin remodeling requirements in the ETV2 regulation of hemangiogenesis (aim 3). The
successful completion of the proposed studies will advance our understanding of how hematopoietic and
EC development is regulated. Ultimately, this knowledge will be instrumental for generating hematopoietic
and ECs from pluripotent stem cells or somatic cell reprogramming and the function of such cells in a wide
range of regenerative medicine applications.

## Key facts

- **NIH application ID:** 10317706
- **Project number:** 2R01HL055337-24A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** KYUNGHEE CHOI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $724,035
- **Award type:** 2
- **Project period:** 1996-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317706

## Citation

> US National Institutes of Health, RePORTER application 10317706, HEMANGIOBLAST DEVELOPMENT AND REGULATION (2R01HL055337-24A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317706. Licensed CC0.

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