# Endothelial cell autonomous mechanisms of blood vessel diameter control

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $434,299

## Abstract

Abstract
Blood vessels are important for the distribution of nutrients and oxygen to all parts of our bodies. A hierarchical
organization of differently sized blood vessels is key for their functionality. Several diseases can affect blood
vessel topologies and diameters, leading to vascular malformations in humans. Previous reports suggested that
increases in blood vessel diameters can be caused by increases in endothelial cell numbers, the cells of the
blood vessels’ inner lining. We established an imaging approach in zebrafish embryos that allows us to precisely
analyze endothelial cell numbers in addition to their shapes and sizes during embryonic development.
Surprisingly, we found that initially the shapes and sizes of endothelial cells were more critical for blood vessel
diameter control than their numbers and that endothelial cell numbers increased only at later stages of vascular
malformation establishment. Importantly, we also found that endothelial shapes and sizes were affected in
mutants of several different genes causing vascular malformations. However, to date it is not known how these
genes affect cell shapes and sizes and how this would impact blood vessel diameters. The aims in this proposal
address this question by analyzing the cellular and molecular components influencing cell shapes and sizes. In
aim 1 we will investigate how the cytoskeleton and its contractile properties affect cellular dimensions and how
this might feedback on blood vessel diameters. We will also investigate whether changing the cytoskeleton and
hence endothelial cell contractility can rescue vascular malformations. In aim 2 we plan to interrogate the
influence of endothelial cell polarity on blood vessel diameters. Endothelial cells have an apical, facing the blood
vessel lumen, and a basolateral membrane domain. At present, we do not know how mutations causing vascular
malformations change apical-basal polarity and how these changes would affect blood vessel diameters. We will
test for these possibilities by examining apical and basolateral polarity in different zebrafish mutants that develop
vascular malformations. We will also investigate how changing apical-basolateral polarity will affect endothelial
cell shapes and sizes in these mutants. Ultimately, we aim to reverse vascular malformations through normalizing
apical-basolateral polarity and endothelial cell contractility and thereby endothelial cell shapes prior to increases
in endothelial cell numbers.

## Key facts

- **NIH application ID:** 9945652
- **Project number:** 1R01HL152086-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Arndt Friedrich Siekmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,299
- **Award type:** 1
- **Project period:** 2020-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9945652

## Citation

> US National Institutes of Health, RePORTER application 9945652, Endothelial cell autonomous mechanisms of blood vessel diameter control (1R01HL152086-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9945652. Licensed CC0.

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