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Coupled myovascular expansion directs cardiac growth and regeneration

Paige DeBenedittis1, Anish Karpurapu1, Albert Henry2,3

  • 1Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Development (Cambridge, England)
|September 22, 2022
PubMed

Insights

Cardiac endothelial cells (CECs) and cardiomyocytes (CMs) coordinate heart growth and regeneration via VEGF-VEGFR2 signaling. Enhancing CECs boosts heart repair, suggesting a therapeutic target for cardiac regeneration.

Area of Science:

  • Cardiovascular Biology
  • Regenerative Medicine
  • Cellular Signaling

Background:

  • Heart regeneration necessitates coordinated proliferation of multiple cardiac cell types, including cardiomyocytes (CMs).
  • The specific interactions and niche formation between different cell types that support CM proliferation remain incompletely understood.
  • Cardiac endothelial cells (CECs) play a critical role in vascularization and tissue development.

Purpose of the Study:

  • To investigate the spatiotemporal coupling between CEC and CM proliferation during neonatal heart development and injury.
  • To elucidate the role of VEGF-VEGFR2 signaling in mediating myovascular expansion and cardiac regeneration.
  • To explore the therapeutic potential of targeting the myovascular niche for heart regeneration.

Main Methods:

  • Profiling proliferation kinetics of CECs and CMs in neonatal mouse hearts.
  • Genetic deletion of VEGFR2 in CECs and pharmacological inhibition of VEGFA.
  • Cryoinjury model to assess cardiac repair and regeneration.
  • Viral vector delivery to boost CEC density post-injury.
  • Mendelian randomization analysis of human genetic data.

Main Results:

  • CEC and CM proliferation are spatiotemporally coupled during neonatal heart growth.
  • VEGF-VEGFR2 signaling is essential for coupled myovascular expansion; its disruption abrogates CEC and CM proliferation.
  • Cryoinjury impairs spatial coupling of CEC and CM proliferation, leading to poor regeneration.
  • Boosting CEC density with VEGFA enhances cardiac regeneration after cryoinjury.
  • Human genetic data show a positive correlation between circulating VEGFA levels and myocardial mass.

Conclusions:

  • Coupled expansion of CECs and CMs is crucial for cardiac growth and regeneration.
  • The myovascular niche, regulated by VEGF-VEGFR2 signaling, is a key determinant of cardiac regenerative capacity.
  • Targeting the myovascular niche, particularly by modulating CECs and VEGFA, holds therapeutic promise for heart regeneration.

Keywords:
Cardiomyocyte proliferationHeart regenerationMouseMyovascular

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