Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling.
BACKGROUND
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.


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 inPolydom-/-embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout ofpolydomin 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 inPolydom-/-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 inPolydom-/-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.
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Nanami
N
Morooka
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Sugiko
S
Futaki
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Ryoko
R
Sato-Nishiuchi
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Masafumi
M
Nishino
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Yuta
Y
Totani
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Chisei
C
Shimono
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Itsuko
I
Nakano
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Hiroyuki
H
Nakajima
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Naoki
N
Mochizuki
From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell Biology (M.N., H.N., N. Mochizuki) and AMED-CREST (N. Mochizuki), National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. sekiguch@protein.osaka-u.ac.jp.
Kiyotoshi
K
Sekiguchi
D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D002450:Cell Communication; D002478:Cells, Cultured; D004487:Edema / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006801:Humans; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D008648:Mesoderm / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013897:Thoracic Duct / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D042702:Angiopoietin-2; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D051858:Forkhead Transcription Factors; C418635:Polydom protein, mouse; D011506:Proteins; C000617888:Svep1 protein, zebrafish; D029961:Zebrafish Proteins; C082078:mesenchyme fork head 1 protein; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
Polydom/Svep1; embryonic development; extracellular matrix; lymphatic capillary; vascular remodeling