# Cxc12 chemokine signaling regulates synchronous development of coronary vessels and myocardium

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2020 · $416,141

## Abstract

Project Summary
The coronary vasculature plays essential roles in maintaining a continuous supply of oxygen
and nutrients to the heart. Coronary heart disease is a major cause of myocardial infarction and
heart failure, which continues to be the leading cause of mortality worldwide. Despite its
importance, the mechanisms that regulate coronary vascularization of the myocardium remain a
major gap in our knowledge. We observed that during zebrafish heart development, coronary
vessels form a close association with a specific subpopulation of cortical cardiomyocytes
marked by the transcription factor Gata4. gata4+ cardiomyocytes follow the tracks of coronary
endothelial cells when they emerge onto the surface of the juvenile zebrafish hearts.
Furthermore, our preliminary data suggest that expression of the Cxcl12b chemokine, a critical
angiogenic factor during zebrafish coronary vessel development, is increased in expanding
gata4+ cardiomyocytes. Moreover, gata4+ cardiomyocytes fail to associate with coronary
vessels in hearts lacking Cxcr4a, the receptor for Cxcl12b. Importantly, adult cxcr4a mutant
zebrafish fail to regenerate after heart injury. We hypothesize that heart development occurs in
two phases that are regulated by temporally distinct mechanisms: newly formed coronary
endothelial cells provide instructive cues, such as paracrine factors, during the emerging phase
to guide gata4+ cardiomyocytes when they emerge, while during the expanding phase, cxcl12b
expression increases in gata4+ cardiomyocytes to attract coronary vessels that are essential for
their morphogenesis/development and regeneration. We propose to 1) To determine how new
coronary vessels guide gata4+ cardiomyocytes to populate the heart ventricle by analyzing
differentially expressed candidate genes identified from RNAseq encoding secreted molecules
(e.g. cxcr4, erbb4) using CRISPR mutant fish lines and a novel explant culture system; 2) To
determine how coronary vessels affect morphogenesis and the regenerative capacity of gata4+
cardiomyocytes during myocardial expansion using multicolor clonal analysis and by
manipulating Cxcl12-Cxcr4 chemokine signaling. We will further determine how cxcl12b
expression is regulated by hypoxia and Gata4. Our proposed study will reveal potential
developmental causes of coronary heart diseases. Furthermore, elucidation of the mechanisms
underlying myocardial vascularization in zebrafish will shed light on potential therapeutic
approaches for humans.

## Key facts

- **NIH application ID:** 9858417
- **Project number:** 5R01HL130172-04
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Ching-Ling E Lien
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,141
- **Award type:** 5
- **Project period:** 2017-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858417

## Citation

> US National Institutes of Health, RePORTER application 9858417, Cxc12 chemokine signaling regulates synchronous development of coronary vessels and myocardium (5R01HL130172-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858417. Licensed CC0.

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