Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 121, Issue 6, Pages 2278-2289Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI46322
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Funding
- CIHR [MOP77756, 62931]
- NIH [1 U01 DK076136-01]
- Terry Fox [TF016002]
- Banting and Best Diabetes Centre
- Wenner-Gren Foundation
- RWTH University of Aachen
- CRC Canada Research Chair Tier II
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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.
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