RRC ID 66024
Author Morooka N, Futaki S, Sato-Nishiuchi R, Nishino M, Totani Y, Shimono C, Nakano I, Nakajima H, Mochizuki N, Sekiguchi K.
Title Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling.
Journal Circ Res
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 α9β1. 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.
Volume 120(8)
Pages 1276-1288
Published 2017-4-14
DOI 10.1161/CIRCRESAHA.116.308825
PMID 28179430
MeSH Angiopoietin-2 / metabolism Animals Calcium-Binding Proteins Cell Adhesion Molecules 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
IF 14.467
Zebrafish Tg(SAGFF27C;UAS:EGFP)
Mice RBRC01828 RBRC01834