Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling

Morooka, N., Futaki, S., Sato-Nishiuchi, R., Nishino, M., Totani, Y., Shimono, C., Nakano, I., Nakajima, H., Mochizuki, N., Sekiguchi, K.
Circulation research   120: 1276-1288 (Journal)
Registered Authors
Mochizuki, Naoki, Nakajima, Hiroyuki
Polydom/SVEP1, embryonic development, extracellular matrix, lymphatic capillary, vascular remodeling
MeSH Terms
  • Angiopoietin-2/metabolism
  • Animals
  • Cell Communication
  • Cells, Cultured
  • Edema/genetics
  • Edema/metabolism
  • Edema/physiopathology
  • Endothelial Cells/metabolism*
  • 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
  • Lymphangiogenesis*
  • Lymphatic Vessels/abnormalities
  • Lymphatic Vessels/metabolism*
  • Lymphatic Vessels/physiopathology
  • Mesoderm/metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Protein Binding
  • Proteins/genetics
  • Proteins/metabolism*
  • 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
28179430 Full text @ Circ. Res.
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 α9β1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development.
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, a transcription factor involved in lymphatic remodeling, was decreased in Polydom(-/-) mice. Polydom bound to the lymphangiogenic factor 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 Angiopoietin-2 and Tie1/Tie2 receptor system.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes