Angiopoietin-1 is essential in mouse vasculature during development and in response to injury

J Clin Invest. 2011 Jun;121(6):2278-89. doi: 10.1172/JCI46322. Epub 2011 May 23.

Abstract

Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.

Publication types

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

MeSH terms

  • Angiopoietin-1 / deficiency
  • Angiopoietin-1 / genetics
  • Angiopoietin-1 / physiology*
  • Animals
  • Blood Vessels / cytology
  • Blood Vessels / embryology*
  • Blood Vessels / injuries*
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Nephropathies / physiopathology
  • Fetal Heart / growth & development
  • Fetal Heart / pathology
  • Gene Expression Regulation, Developmental
  • Humans
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / pathology
  • Liver / blood supply
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Neovascularization, Pathologic / embryology
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / physiopathology
  • Neovascularization, Physiologic / physiology*
  • Pericytes / metabolism
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptor, TIE-1 / physiology
  • Receptor, TIE-2
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / physiology
  • Wound Healing / physiology*

Substances

  • Angiopoietin-1
  • Angpt1 protein, mouse
  • Recombinant Fusion Proteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor, TIE-1
  • Receptor, TIE-2
  • Tek protein, mouse