Loss of collagen XVIII enhances neovascularization and vascular permeability in atherosclerosis

Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts, United States
Circulation (Impact Factor: 14.43). 10/2004; 110(10):1330-6. DOI: 10.1161/01.CIR.0000140720.79015.3C
Source: PubMed


Plaque neovascularization is thought to promote atherosclerosis; however, the mechanisms of its regulation are not understood. Collagen XVIII and its proteolytically released endostatin fragment are abundant proteoglycans in vascular basement membranes and the walls of major blood vessels. We hypothesized that collagen XVIII in the aortic wall inhibits the proliferation and intimal extension of vasa vasorum.
To test our hypothesis, we bred collagen XVIII-knockout (Col18a1(-/-)) mice into the atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) strain. After 6 months on a cholesterol diet, aortas from ApoE(-/-);Col18a1(-/-) and ApoE(-/-);Col18a1(+/-) heterozygote mice showed increased atheroma coverage and enhanced lipid accumulation compared with wild-type littermates. We observed more extensive vasa vasorum and intimal neovascularization in knockout but not heterozygote aortas. Endothelial cells sprouting from Col18a1(-/-) aortas were increased compared with heterozygote and wild-type aortas. In contrast, vascular permeability of large and small blood vessels was enhanced with even heterozygous loss of collagen XVIII but was not suppressed by increasing serum endostatin to wild-type levels.
Our results identify a previously unrecognized function for collagen XVIII that maintains vascular permeability. Loss of this basement membrane proteoglycan enhances angiogenesis and vascular permeability during atherosclerosis by distinct gene-dose-dependent mechanisms.

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    • "Therefore, in this animal model it is possible that elevated levels of endostatin occurred in response to myocardial injury. Furthermore, downregulation of collagen XVIII, which is cleaved to generate endostatin, has been reported to promote atherosclerosis progression in a mouse model [20]. Of note recombinant endostatin has been reported to inhibit atherosclerosis progression in the same mouse model [21]. "
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    ABSTRACT: Objectives. A cleavage fragment of collagen XVIII, endostatin, is released into the circulation and has been demonstrated to have antiangiogenic effects in animal models. We hypothesized that circulating endostatin would be increased in patients with symptoms of lower limb peripheral artery disease. Design. Cross-sectional study. Participants. Community dwelling older men. Measurements. Intermittent claudication was defined using the Edinburgh Claudication Questionnaire (ECQ). Serum endostatin was measured by a commercial ELISA. The association of serum endostatin with intermittent claudication was examined using logistic regression adjusting for age, diabetes, hypertension, dyslipidemia, coronary heart disease, and stroke. Results. Serum endostatin was measured in 1114 men who completed the ECQ. 106 men had intermittent claudication, 291 had atypical pain, and 717 had no lower limb pain. Mean (±standard deviation) serum endostatin concentrations (ng/mL) were 145.22 ± 106.93 for men with intermittent claudication, 129.11 ± 79.80 for men with atypical pain, and 116.34 ± 66.57 for men with no lower limb pain; P < 0.001. A 70 ng/mL increase in endostatin was associated with a 1.17-fold rise in the adjusted odds of having intermittent claudication (OR 1.17, 95% confidence interval 1.00–1.37, and P = 0.050). Conclusions. Serum endostatin is raised in older men who have symptoms of intermittent claudication. The role of endostatin in the genesis and outcome of peripheral artery disease requires further investigation.
    Disease markers 01/2014; 2014:298239. DOI:10.1155/2014/298239 · 1.56 Impact Factor
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    • "Systemic loss-of-function alleles in perlecan and agrin are lethal in mice [5], [6], [7]. In contrast, Col18-deficient mice (Col18a1−/−) are viable but exhibit major ocular defects including abnormal retinal vessel development and poor anchoring of vitreal collagen fibrils to the inner lining membrane of the retina [8], [9], [10]. Col18-deficiency also leads to increased vascular permeability of large and small blood vessels and thickening of basement membranes in the heart, kidney, and skin [9], [11]. "
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    ABSTRACT: Lipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism. We examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia. This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.
    PLoS ONE 11/2010; 5(11):e13919. DOI:10.1371/journal.pone.0013919 · 3.23 Impact Factor
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    • "The aortic tissue is among the most abundant tissue sources of collagen XVIII [20] and also contains Type I and Type III collagen. Karen et al., 2004 [21] have hypothesized that collagen XVIII is degraded during atherosclerosis and that loss of this vessel wall proteoglycan promotes the proliferation of vasa vasorum into the intima of atheromas. There studies provide genetic evidence that loss of collagen XVIII promotes atherosclerosis. "
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