A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration

Cell. 2019 Feb 21;176(5):1128-1142.e18. doi: 10.1016/j.cell.2018.12.023. Epub 2019 Jan 24.


Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.

Keywords: CXCL12; arterialization; arteriogenesis; collateral arteries; endothelial cells; heart regeneration; myocardial infarction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn / growth & development
  • Chemokine CXCL12 / metabolism
  • Collateral Circulation / physiology*
  • Coronary Vessels / growth & development
  • Endothelial Cells / metabolism
  • Female
  • Heart / growth & development*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / physiology
  • Receptors, CXCR4 / metabolism
  • Regeneration / physiology*
  • Signal Transduction


  • CXCL12 protein, human
  • CXCR4 protein, human
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Receptors, CXCR4