# Embryonic origins of endothelial heterogeneity

> **NIH NIH R35** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $1,005,000

## Abstract

PROJECT SUMMARY
Endothelial heterogeneity is a defining characteristic of the mature circulatory system. Endothelial
cells that line capillary beds or other small caliber vessels have distinct phenotypes and molecular
signatures that relate to their various functions in different anatomical locations. In larger vessels,
there are clear molecular and phenotypic differences between arterial and venous endothelial cells.
In all of these cases, endothelial differentiation is essential for normal physiological function of the
circulatory system. Importantly, endothelial heterogeneity can have a major influence on the site and
severity of vascular disease. Thus, a better understanding of how endothelial cell types are
determined is highly relevant. For the past 15 years, we have used the zebrafish as a model system
to investigate basic mechanisms of vascular morphogenesis and patterning during embryonic
development. Our efforts have revealed new insights into how blood vessels are formed and
underscore the importance of endothelial differentiation in this process. Importantly, we have found
that endothelial cell differentiation is a primary step that is essential for blood vessel formation and
assembly. However, the developmental origins of endothelial identities and the signaling pathways
that drive differentiation are largely unknown. In the studies proposed here, we will apply a number of
traditional developmental biology approaches coupled with cutting-edge molecular techniques to
define the hierarchy of endothelial ontogeny during embryonic development. Through Cre/lox lineage
tracing we will identify where and when endothelial cell types are established. In parallel, we will
apply single cell RNA sequencing on endothelial progenitors at multiple developmental stages to
identify transcriptome signatures that define endothelial subtypes. At the same time, efforts to identify
enhancer elements flanking subtype-specific genes will contribute to our knowledge of transcriptional
regulatory pathways and upstream signals that drive differentiation. Finally, we will continue to
investigate the link between endothelial differentiation and vascular morphogenesis through functional
interrogation of subtype specific genes using knockout zebrafish models generated through genome
editing. Together, our efforts will define the developmental endothelial hierarchy and allow us to
identify essential signaling pathways responsible for endothelial heterogeneity.

## Key facts

- **NIH application ID:** 10077348
- **Project number:** 5R35HL140017-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** NATHAN D LAWSON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,005,000
- **Award type:** 5
- **Project period:** 2018-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077348

## Citation

> US National Institutes of Health, RePORTER application 10077348, Embryonic origins of endothelial heterogeneity (5R35HL140017-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10077348. Licensed CC0.

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