VE-statin/egfl7 regulates vascular elastogenesis by interacting with lysyl oxidases.
We previously characterized VE-statin/egfl7, a protein that is exclusively secreted by endothelial cells and modulates smooth muscle cell migration. Here, we show that VE-statin/egfl7 is the first known natural negative regulator of vascular elastogenesis. Transgenic mice, expressing VE-statin/egfl7 under the control of keratin-14 promoter, showed an accumulation of VE-statin/egfl7 in arterial walls where its presence correlated with an impaired organization of elastic fibres. In vitro, fibroblasts cultured in the presence of VE-statin/egfl7 were unable to deposit elastic fibres due to a deficient conversion of soluble tropoelastin into insoluble mature elastin. VE-statin/egfl7 interacts with the catalytic domain of lysyl oxidase (LOX) enzymes and, in endothelial cells, endogenous VE-statin/egfl7 colocalizes with LoxL2 and inhibits elastic fibre deposition. In contrast, mature elastic fibres are abundantly deposited by endothelial cells that are prevented from producing endogenous VE-statin/egfl7. We propose a model where VE-statin/egfl7 produced by endothelial cells binds to the catalytic domains of enzymes of the LOX family in the vascular wall, thereby preventing the crosslink of tropoelastin molecules into mature elastin polymers and regulating vascular elastogenesis.
Lelièvre
Etienne
E
CNRS, UMR 8161, Institut de Biologie de Lille, Equipe labellisée La Ligue 2005, Université de Lille I, Université de Lille II, Institut Pasteur de Lille, Lille, France.
Hinek
Aleksander
A
Lupu
Florea
F
Buquet
Christelle
C
Soncin
Fabrice
F
Mattot
Virginie
V
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000201:enzymology*; D002135:Calcium-Binding Proteins; D020134:Catalytic Domain; D002460:Cell Line; D066255:EGF Family of Proteins; D004547:Elastic Tissue / Q000378:metabolism; D004549:Elastin / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D008249:Protein-Lysine 6-Oxidase / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012868:Skin Abnormalities / Q000473:pathology; D014158:Transcription, Genetic; D014333:Tropoelastin / Q000235:genetics
D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C479627:Egfl7 protein, mouse; D011506:Proteins; D014333:Tropoelastin; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase