# Signaling by beta 1 integrins regulates ventricular wall morphogenesis and compaction

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $469,674

## Abstract

Cardiovascular diseases are the leading causes of morbidity and mortality in developed countries. One such
disease is left ventricular noncompaction (LVNC, OMIM604169). The prevalence of LVNC reportedly ranged
from 0.01% to 0.3%, and is higher in patients with heart failure, reportedly 3% to 4%. Genetic inheritance
occurs in at least 30–50% of patients and genes that cause LVNC include the genes that encode sarcomeric or
cytoskeletal proteins and Notch signaling pathway genes. In LVNC, trabeculae fail to undergo compaction.
Trabeculae are sheet-like structures extending from the myocardium to the heart lumen that function to
increase surface area when the coronary circulation system is not developed yet. A lack of trabeculation
causes embryonic lethality, and excess trabeculation causes LVNC and heart failure in humans. Our studies
demonstrated that the orientated cell division and directional migration of cardiomyocytes in the single-cell-
thick myocardium contribute to trabecular initiation by forming a multiple-layer myocardium. Then endocardial
cells (EndCs) invade the multiple layered myocardium and allocate cardiomyocytes to form trabeculae before
E9.5. Many mutations of contractile protein genes correlate with LVNC, and it has been speculated that the
contractile function of the myocardium is required for ventricular compaction; however, no genetic models have
been made to test this hypothesis. The subsequent questions in this field will be what are the mechanisms that
regulate the trabecular formation, de novo trabeculation, and ventricular compaction. Our preliminary data
show that early the Itgb1 gene causes defects in trabecular formation, growth, Notch1
activation and deposition of Fibronectin (Fn), and late deletion causes defects in compaction and Notch1
activation. Furthermore, global deletion of the Itga5 gene or Fn1 gene causes defects in cardiovascular
morphogenesis, but early lethality prevented the study of their functions in trabecular morphogenesis. Our
heart-specific deletion of
preliminary data show that heart-specific Itga6 gene (encoding integrin α6 subunit or α6), which
is expressed specifically in the trabecular zone during compaction, reduces cardiac contractile function.
Therefore, our central hypothesis is that integrin α5β1 and α6β1 have distinct functions in cardiac
morphogenesis with α5β1 regulating trabecular formation and growth, and integrin α6β1 regulating ventricular
contraction and the subsequent compaction and Notch1 activation. There are two aims to test the hypothesis.
Genetic tools such as trabecular specific and compact zone specific Cre lines will be used to test these
hypotheses. We have developed some unique expertise, e.g., single cell lineage tracing assay to study the
mechanisms of trabeculation; ECHO to measure the contractility of embryonic hearts treated with drug or
vehicle; rAAV9 system to rescue the LVNC defect. Completion of the studies will determine whether α5β1 axis
regulates the trabec...

## Key facts

- **NIH application ID:** 10304653
- **Project number:** 7R01HL121700-07
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Mingfu Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,674
- **Award type:** 7
- **Project period:** 2014-11-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304653

## Citation

> US National Institutes of Health, RePORTER application 10304653, Signaling by beta 1 integrins regulates ventricular wall morphogenesis and compaction (7R01HL121700-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10304653. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*