ALK1 signaling regulates early postnatal lymphatic vessel development.
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-beta 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.
Niessen
Kyle
K
Department of Tumor Biology and Angiogenesis, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Zhang
Gu
G
Ridgway
John Brady
JB
Chen
Hao
H
Yan
Minhong
M
D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism
D008024:Ligands; D040321:Vascular Endothelial Growth Factor Receptor-3; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse