The Dll4/Notch pathway controls postangiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow

Blood. 2011 Jun 16;117(24):6728-37. doi: 10.1182/blood-2010-08-302067. Epub 2011 Apr 15.


Blood vessel remodeling is crucial to the formation of the definitive vasculature, but little is known about the mechanisms controlling this process. We show that Delta-like ligand 4 (Dll4)/Notch pathway regulates vessel regression in normal pathologic conditions. Genetic and pharmacologic inhibition of Dll4/Notch prevented retinal capillary regression in the oxygen-induced retinopathy (OIR) model and during normal development. Deletion of the Notch-regulated ankyrin repeat protein, a negative regulator of the Notch pathway, produced an opposite phenotype. Inhibition of Dll4/Notch reduced vessel occlusion, maintaining blood flow that is essential for survival of microvessels. Dll4/Notch inhibition up-regulated the expression of vasodilators adrenomedullin and suppressed the expression of vasoconstrictor angiotensinogen. Angiotensin II induced rapid nonperfusion and regression of developing retinal capillaries, whereas Ace1 and AT1 inhibitors and adrenomedullin attenuated vasoobliteration in OIR, indicating that both pathways are involved in modulating vessel remodeling. In contrast, inhibition of vascular endothelial growth factor-A (VEGF-A) did not result in a pervasive loss of retinal capillaries, demonstrating that reduced expression of VEGF-A is not the proximate cause of capillary regression in OIR. Modulation of VEGF-A and Dll4/Notch signaling produced distinct changes in blood vessel morphology and gene expression, indicating that these pathways can have largely independent functions in vascular remodeling.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Animals, Newborn
  • Atrophy / genetics
  • Blood Vessels / metabolism
  • Blood Vessels / pathology*
  • Blood Vessels / physiology*
  • CHO Cells
  • Calcium-Binding Proteins
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neovascularization, Physiologic / genetics
  • Neovascularization, Physiologic / physiology
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptor, Notch1 / physiology*
  • Regeneration / genetics
  • Regeneration / physiology
  • Regional Blood Flow / genetics*
  • Regional Blood Flow / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Vasoconstriction / genetics*
  • Vasoconstriction / physiology


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Notch1 protein, mouse
  • Receptor, Notch1