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

• Published in: The Journal of clinical investigation 2011-06, Vol.121 (6), p.2278-2289
• Main Authors: Jeansson, Marie, Gawlik, Alexander, Anderson, Gregory, Li, Chengjin, Kerjaschki, Dontscho, Henkelman, Mark, Quaggin, Susan E
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiopoietin-1 - deficiency; Angiopoietin-1 - genetics; Angiopoietin-1 - physiology; Animals; Biomedical research; Blood Vessels - cytology; Blood Vessels - embryology; Blood Vessels - injuries; Cloning; Diabetes; Diabetes Mellitus, Experimental - physiopathology; Diabetic Nephropathies - physiopathology; Embryos; Fetal Heart - growth & development; Fetal Heart - pathology; Gene Expression Regulation, Developmental; Genotype & phenotype; Heart; Humans; Kidney Glomerulus - blood supply; Kidney Glomerulus - pathology; Kinases; 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
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/jci46322

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.