Loss of Collagen XVIII Enhances Neovascularization and Vascular Permeability in Atherosclerosis

Moulton, Karen S.; Olsen, Bjørn R.; Sonn, Silvia; Fukai, Naomi; Zurakowski, David; Zeng, Xiangzhong

doi:10.1161/01.cir.0000140720.79015.3c

Cited by 127 publications

(97 citation statements)

References 36 publications

(47 reference statements)

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“…1,[12][13][14][15][16]19,[25][26][27] Whereas several studies on tumor progression, atherosclerosis, cutaneous wound healing, and visual function have demonstrated that endogenous Col 18/endostatin is a potent factor in the inhibition of angiogenesis and in matrix remodeling, 7,8,10,18,28,29 little attention has been paid to its potential function in a model of inflammatory renal disease.…”

Section: Discussionmentioning

confidence: 99%

Lack of Collagen XVIII/Endostatin Exacerbates Immune-Mediated Glomerulonephritis

Hamano

Okude²,

Shirai³

et al. 2010

Journal of the American Society of Nephrology

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Collagen XVIII is a component of the highly specialized extracellular matrix associated with basement membranes of epithelia and endothelia. In the normal kidney, collagen XVIII is distributed throughout glomerular and tubular basement membranes, mesangial matrix, and Bowman's capsule. Proteolytic cleavage within its C-terminal domain releases the fragment endostatin, which has antiangiogenic properties. Because damage to the glomerular basement membrane (GBM) accompanies immune-mediated renal injury, we investigated the role of collagen XVIII/endostatin in this disorder. We induced anti-GBM glomerulonephritis in collagen XVIII ␣1-null and wild-type mice and compared the resulting matrix accumulation, inflammation, and capillary rarefaction. Anti-GBM disease upregulated collagen XVIII/endostatin expression within the GBM and Bowman's capsule of wild-type mice. Collagen XVIII/endostatin-deficient mice developed more severe glomerular and tubulointerstitial injury than wild-type mice. Collagen XVIII/endostatin deficiency altered matrix remodeling, enhanced the inflammatory response, and promoted capillary rarefaction and vascular endothelial cell damage, but did not affect endothelial proliferation. Supplementing collagen XVIII-deficient mice with exogenous endostatin did not affect the progression of anti-GBM disease. Taken together, these results suggest that collagen XVIII/endostatin preserves the integrity of the extracellular matrix and capillaries in the kidney, protecting against progressive glomerulonephritis.

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Section: Discussionmentioning

confidence: 99%

Lack of Collagen XVIII/Endostatin Exacerbates Immune-Mediated Glomerulonephritis

Hamano

Okude²,

Shirai³

et al. 2010

Journal of the American Society of Nephrology

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“…Moreover, on a specific background, Col18a1 −/− mice have increased susceptibility to hydrocephalus associated with broadening of the epithelial BM of the choroid plexuses (10). Curiously, these mice also display postprandial hyperlipidemia (11) and, on an apolipoprotein E (ApoE) −/− background, develop severe atherosclerosis because of increased plaque angiogenesis and permeability of the vasculature to lipids (12). Thus, collagen XVIII is obligatory for controlling blood vessel formation in the eye, and may also partake in BM or cell-signaling functions in extraocular tissues.…”

mentioning

confidence: 99%

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

Aikio

Elamaa

Vicente

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzledlike sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

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“…The proteasesusceptible N terminus of collagen XVIII proteins are depleted in early-stage atheromas compared with the ES fragment; therefore, we tested whether ES modifies lipoprotein retention to biglycan and to SEM (18,19). We now show that ES interacts with biglycan and LDL and interferes with LDL retention to biglycan.…”

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confidence: 83%

Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis

Zeng

Chen

Miller

et al. 2005

Journal of Lipid Research

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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 ␣ 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. Lipid accumulation and macrophage-derived foam cells are prominent features of atherosclerotic plaques. The response-to-retention hypothesis proposes that serum lipoproteins are retained by proteoglycans in the subendothelial matrix (SEM) and subsequently modified and taken up by macrophages to form foam cells that constitute the fatty streak type of atheroma (1-3). Biglycan, a dermatan sulfate proteoglycan in human and mouse atheromas, binds LDL by ionic interactions involving specific basic amino acids in apolipoprotein B-100 and sulfated sugar modifications of biglycan (4-6). LDL association or aggregation with arterial wall proteoglycans increases rates of LDL oxidation and macrophage uptake (7,8). Mice expressing mutant apolipoprotein B-100 produce LDL particles with lower proteoglycan affinity and develop less atherosclerosis (9, 10). Dermatan sulfate and chondroitin sulfate proteoglycans such as biglycan and versican are increased, whereas heparan sulfate proteoglycans are reduced in atheromas compared with normal blood vessels (4, 11). Therefore, relative changes in the matrix composition of atheromas could enhance LDL retention of SEM during atherosclerosis.The aorta is an abundant tissue source of the heparan sulfate proteoglycan collagen XVIII and its proteolytically released endostatin (ES) fragment, which has previously been shown to inhibit angiogenesis in cancer and atherosclerosis models (12)(13)(14)(15). The ES portion of collagen XVIII has no attachment sites for glycosaminoglycans (GAGs) but has high affinity for heparin, which is necessary for its antiangiogenesis functions (16). Our recent data showed that collagen XVIII is differ...

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Loss of Collagen XVIII Enhances Neovascularization and Vascular Permeability in Atherosclerosis

Cited by 127 publications

References 36 publications

Lack of Collagen XVIII/Endostatin Exacerbates Immune-Mediated Glomerulonephritis

Lack of Collagen XVIII/Endostatin Exacerbates Immune-Mediated Glomerulonephritis

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis

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