Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis.
Retention of lipoproteins to proteoglycans in the subendothelial matrix (SEM) is an early event in atherosclerosis. We recently reported that collagen XVIII and its proteolytically released fragment endostatin (ES) are differentially depleted in blood vessels affected by atherosclerosis. Loss of collagen XVIII/ES in atherosclerosis-prone mice enhanced plaque neovascularization and increased the vascular permeability to lipids by distinct mechanisms. Impaired endothelial barrier function increased the influx of lipoproteins across the endothelium; however, we hypothesized that enhanced retention might be a second mechanism leading to the increased lipid content in atheromas lacking collagen XVIII. We now demonstrate a novel property of ES that binds both the matrix proteoglycan biglycan and LDL and interferes with LDL retention to biglycan and to SEM. A peptide encompassing the alpha coil in the ES crystal structure mediates the major blocking effect of ES on LDL retention. ES inhibits the macrophage uptake of biglycan-associated LDL indirectly by interfering with LDL retention to biglycan, but it has no direct effect on the macrophage uptake of native or modified lipoproteins. Thus, loss of ES in advanced atheromas enhances lipoprotein retention in SEM. Our data reveal a third protective role of this vascular basement membrane component during atherosclerosis.
Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, MA 02115, USA.
Xiaokun
X
Zeng
Joshua
J
Chen
Yury I
YI
Miller
Kashi
K
Javaherian
Karen S
KS
Moulton
D000818:Animals; D001011:Aorta / Q000737:chemistry; D001161:Arteriosclerosis / Q000378:metabolism*; D001485:Basement Membrane / Q000378:metabolism; D058578:Biglycan; D001665:Binding Sites; D001667:Binding, Competitive; D043170:Collagen Type XVIII / Q000378:metabolism; D043169:Endostatins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology*; D004727:Endothelium / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D011509:Proteoglycans / Q000378:metabolism*; D011994:Recombinant Proteins; D014471:Umbilical Veins
C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; D043170:Collagen Type XVIII; D043169:Endostatins; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D011994:Recombinant Proteins