BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
Authors: Andrea Caporali; Magnus Bäck; Mat J Daemen; Imo E Hoefer; Elizabeth A Jones; Esther Lutgens; Christian M Matter; Marie-Luce Bochaton-Piallat; Arndt F Siekmann; Judith C Sluimer; Sabine Steffens; José Tuñón; Cecile Vindis; Jolanda J Wentzel; Seppo Ylä-Herttuala; Paul C Evans Journal: Cardiovasc Res Date: 2018-09-01 Impact factor: 10.787
Authors: Xiaoyan Yin; Subha Subramanian; Shih-Jen Hwang; Christopher J O'Donnell; Caroline S Fox; Paul Courchesne; Pieter Muntendam; Neal Gordon; Aram Adourian; Peter Juhasz; Martin G Larson; Daniel Levy Journal: Arterioscler Thromb Vasc Biol Date: 2014-02-13 Impact factor: 8.311
Authors: Edward B Neufeld; Leah M Zadrozny; Darci Phillips; Angel Aponte; Zu-Xi Yu; Robert S Balaban Journal: Atherosclerosis Date: 2014-01-08 Impact factor: 5.162
Authors: C B Rygh; G Løkka; R Heljasvaara; T Taxt; T Pavlin; R Sormunen; T Pihlajaniemi; F R Curry; O Tenstad; R K Reed Journal: J Physiol Date: 2013-11-11 Impact factor: 5.182