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Circ Res ; 120(8): 1276-1288, 2017 Apr 14.
Article in English | MEDLINE | ID: mdl-28179430

ABSTRACT

RATIONALE: Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. OBJECTIVE: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9ß1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. METHODS AND RESULTS: We generated Polydom-deficient mice. Polydom-/- mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom-/- embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in Polydom-/- mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in Polydom-/- mice. CONCLUSIONS: Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.


Subject(s)
Endothelial Cells/metabolism , Lymphangiogenesis , Lymphatic Vessels/metabolism , Proteins/metabolism , Angiopoietin-2/metabolism , Animals , Calcium-Binding Proteins , Cell Adhesion Molecules , Cell Communication , Cells, Cultured , Edema/genetics , Edema/metabolism , Edema/physiopathology , Endothelial Cells/pathology , Endothelium, Lymphatic/abnormalities , Endothelium, Lymphatic/metabolism , Endothelium, Lymphatic/physiopathology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Developmental , Genotype , Humans , Lymphatic Vessels/abnormalities , Lymphatic Vessels/physiopathology , Mesoderm/metabolism , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Protein Binding , Proteins/genetics , Receptor, TIE-1/genetics , Receptor, TIE-1/metabolism , Receptor, TIE-2/genetics , Receptor, TIE-2/metabolism , Signal Transduction , Thoracic Duct/abnormalities , Thoracic Duct/metabolism , Thoracic Duct/physiopathology , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
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