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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-1 / deficiency
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Angiopoietin-1 / genetics
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Angiopoietin-1 / physiology*
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Animals
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Blood Vessels / cytology
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Blood Vessels / embryology*
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Blood Vessels / injuries*
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Diabetes Mellitus, Experimental / physiopathology
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Diabetic Nephropathies / physiopathology
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Fetal Heart / growth & development
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Fetal Heart / pathology
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Gene Expression Regulation, Developmental
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Humans
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Kidney Glomerulus / blood supply
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Kidney Glomerulus / pathology
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Liver / blood supply
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Mice
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Mice, Knockout
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Myocytes, Cardiac / pathology
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Myocytes, Cardiac / physiology
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Neovascularization, Pathologic / embryology
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / physiopathology
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Neovascularization, Physiologic / physiology*
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Pericytes / metabolism
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Receptor Protein-Tyrosine Kinases / physiology
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Receptor, TIE-1 / physiology
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Receptor, TIE-2
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Wound Healing / physiology*
Substances
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Angiopoietin-1
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Angpt1 protein, mouse
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Recombinant Fusion Proteins
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Receptor Protein-Tyrosine Kinases
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Receptor, TIE-1
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Receptor, TIE-2
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Tek protein, mouse