ALK1 signaling regulates early postnatal lymphatic vessel development
Open Access
- 25 February 2010
- journal article
- Published by American Society of Hematology in Blood
- Vol. 115 (8), 1654-1661
- https://doi.org/10.1182/blood-2009-07-235655
Abstract
In vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.Keywords
This publication has 35 references indexed in Scilit:
- Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial CellsJournal of Biological Chemistry, 2009
- Mechanisms of TGF-β Signaling from Cell Membrane to the NucleusCell, 2003
- BMP signaling is required for septation of the outflow tract of the mammalian heartDevelopment, 2003
- Prox1 is a master control gene in the program specifying lymphatic endothelial cell fateDevelopmental Dynamics, 2002
- Angiopoietin-2 Is Required for Postnatal Angiogenesis and Lymphatic Patterning, and Only the Latter Role Is Rescued by Angiopoietin-1Developmental Cell, 2002
- An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotypeThe EMBO Journal, 2002
- Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3Nature Medicine, 2001
- Arteriovenous malformations in mice lacking activin receptor-like kinase-1Nature Genetics, 2000
- Familial Primary Pulmonary Hypertension (Gene PPH1) Is Caused by Mutations in the Bone Morphogenetic Protein Receptor–II GeneAmerican Journal of Human Genetics, 2000
- BMP Type II Receptor Is Required for Gastrulation and Early Development of Mouse EmbryosDevelopmental Biology, 2000