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Mechanisms of endothelial cell differentiation during vasculogenesis

Award Number: K99HL179259
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/04/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Mechanisms of endothelial cell differentiation during vasculogenesis - PROJECT SUMMARY/ ABSTRACT Blood vessels are the earliest organs formed during embryonic development, and the embryonic cardiovas- cular system is required for nutrient exchange and organogenesis. As early as mouse embryonic day (E) 7.5 in the extraembryonic yolk sac blood islands and embryos, mesodermal precursors undergo the first cell fate de- cision to form the endothelial cell (EC) lineage. ECs further differentiate into arterial, venous, and lymphatic subtypes that are necessary to build the vascular system. However, the clonal relationships and spatial origins of EC subtypes that form the vasculature are poorly defined, and the mechanisms of EC specification and dif- ferentiation in vivo remain incompletely understood, posing a barrier to vascular regenerative medicine. Etv2, an ETS-family transcription factor, is a master regulator of EC specification. Etv2 is transiently ex- pressed in mesoderm progenitors in the yolk sac and developing mouse embryo from E7.5 - E9.5. Mice lacking Etv2 fail to develop blood or vasculature, and Etv2 is responsible for endothelial and hematopoietic lineage specification. Conversely, forced expression of Etv2 induces EC reprogramming. We have carefully interro- gated mechanisms by which ETV2 promotes EC specification in mesoderm progenitors derived from human induced pluripotent stem cells (iPSCs), using scRNA-seq, scATAC-seq, CUT&RUN, and functional CRISPR screens. Novel observations included: (1) the strength or timing of ETV2 expression influenced arteriovenous EC differentiation; (2) in addition to stimulating EC specification, ETV2 also suppressed specification of other mesodermal lineages; and (3) ETV2 suppression of alternative fates required its recruitment of the transcrip- tional repressor REST. These observations lead to our central hypothesis that ETV2 drives EC specification and arteriovenous differentiation, with REST cooperating with ETV2 to restrict alternative lineages during em- bryonic vasculogenesis. To track cell state transitions and fate of Etv2-expressing cells during vasculogenesis, we will integrate cut- ting edge single cell, spatial transcriptomics, and barcoded lineage tracing approaches to track the progeny of Etv2-expressing progenitors. To focus our efforts, in Aim 1 we will study the initial steps of vessel formation in the yolk sac. We will perform spatial and clonal analysis of Etv2-lineage cells during early yolk sac vasculogen- esis and late vascular plexus remodeling. To determine the role of Rest in Etv2-directed EC specification, in Aim 2 we will determine the effect of Rest inactivation on vasculogenesis and Etv2-lineage diversification, un- cover the Rest-Etv2 transcriptional regulatory network, and identify Rest-regulated genes and TFs in Etv2-line- age progenitors required for EC specification. The work will produce a high-resolution phylogenetic tree of vas- cular development originating from individual Etv2+ progenitors and bring new insights into the molecular mechanisms that direct EC subtype differentiation, informing future efforts in vascular regeneration.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $139,822 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	5/7/2026	NEW	$139,822
														Subtotal = $139,822

Grand Total All Awards = $139,822

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Mechanisms of endothelial cell differentiation during vasculogenesis

Award Number: K99HL179259

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/04/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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