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(Circulation. 2004;110:1330-1336.)
© 2004 American Heart Association, Inc.

Original Articles

Loss of Collagen XVIII Enhances Neovascularization and Vascular Permeability in Atherosclerosis

Karen S. Moulton, MD; Bjorn R. Olsen, MD, PhD; Silvia Sonn, BA; Naomi Fukai, MD, PhD; David Zurakowski, PhD; Xiaokun Zeng, PhD

From the Vascular Biology Research Program, Department of Surgery (K.S.M., S.S., X.Z.), and Departments of Orthopaedic Surgery and Biostatistics (D.Z.), Children’s Hospital Medical Center; the Cardiovascular Division, Brigham and Women’s Hospital (K.S.M.); and the Department of Cell Biology, Harvard Medical School (B.R.O., N.F.), Boston, Mass.

Correspondence to Karen S. Moulton, Vascular Biology Research Program, Department of Surgery, Children’s Hospital Medical Center, 300 Longwood Ave, Boston, MA 02115. E-mail karen.moulton{at}childrens.harvard.edu

Received March 25, 2004; revision received May 24, 2004; accepted May 25, 2004.

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.

Key Words: angiogenesis • atherosclerosis • extracellular matrix • permeability • vasa vasorum

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