Article

Loss of collagen XVIII enhances neovascularization and vascular permeability in atherosclerosis.

Vascular Biology Research Program, Department of Surgery, Children's Hospital Medical Center, 300 Longwood Ave, Boston, MA 02115, USA.
Circulation (impact factor: 14.74). 10/2004; 110(10):1330-6. DOI:10.1161/01.CIR.0000140720.79015.3C pp.1330-6
Source: PubMed

ABSTRACT 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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Keywords

aortic wall inhibits
 
atheroma coverage
 
atherosclerosis-prone apolipoprotein E-deficient
 
collagen XVIII
 
collagen XVIII-knockout
 
distinct gene-dose-dependent mechanisms
 
endostatin fragment
 
Endothelial cells sprouting
 
extensive vasa vasorum
 
intimal neovascularization
 
lipid accumulation
 
maintains vascular permeability
 
major blood vessels
 
Plaque neovascularization
 
serum endostatin
 
small blood vessels
 
vasa vasorum
 
vascular basement membranes
 
wild-type levels
 
wild-type littermates