Published Online
on August 16, 2004

A more recent version of this article appeared on September 7, 2004

This Article Full Text (PDF) All Versions of this Article: 110/10/1330    most recent 01.CIR.0000140720.79015.3Cv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moulton, K. S. Articles by Zeng, X. Search for Related Content PubMed PubMed Citation Articles by Moulton, K. S. Articles by Zeng, X. Related Collections Angiogenesis Animal models of human disease Pathophysiology Mechanism of atherosclerosis/growth factors

Submitted on March 25, 2004
Revised on May 24, 2004
Accepted on May 25, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: karen.moulton{at}childrens.harvard.edu.

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

This article has been cited by other articles:

				S. Roy, S. Khanna, C. Rink, S. Biswas, and C. K. Sen Characterization of the acute temporal changes in excisional murine cutaneous wound inflammation by screening of the wound-edge transcriptome Physiol Genomics, July 1, 2008; 34(2): 162 - 184. [Abstract] [Full Text] [PDF]

				G. R. Romeo, K. S. Moulton, and A. Kazlauskas Attenuated Expression of Profilin-1 Confers Protection From Atherosclerosis in the LDL Receptor Null Mouse Circ. Res., August 17, 2007; 101(4): 357 - 367. [Abstract] [Full Text] [PDF]

				B. Doyle and N. Caplice Plaque Neovascularization and Antiangiogenic Therapy for Atherosclerosis J. Am. Coll. Cardiol., May 29, 2007; 49(21): 2073 - 2080. [Abstract] [Full Text] [PDF]

				M. M. Fuster, L. Wang, J. Castagnola, L. Sikora, K. Reddi, P. H.A. Lee, K. A. Radek, M. Schuksz, J. R. Bishop, R. L. Gallo, et al. Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis J. Cell Biol., May 7, 2007; 177(3): 539 - 549. [Abstract] [Full Text] [PDF]

				L. Zhao, J. A. Hall, N. Levenkova, E. Lee, M. K. Middleton, A. M. Zukas, D. J. Rader, J. J. Rux, and E. Pure CD44 Regulates Vascular Gene Expression in a Proatherogenic Environment Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 886 - 892. [Abstract] [Full Text] [PDF]

				J.-S. Shao, J. Cai, and D. A. Towler Molecular Mechanisms of Vascular Calcification: Lessons Learned From The Aorta Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1423 - 1430. [Abstract] [Full Text] [PDF]

				C. Iribarren, L. J Herrinton, J. A Darbinian, L. Tamarkin, D. Malinowski, J. H Vogelman, N. Orentreich, and D. Baer Does the association between serum endostatin, an endogenous anti-angiogenic protein, and acute myocardial infarction differ by race? Vascular Medicine, February 1, 2006; 11(1): 13 - 20. [Abstract] [PDF]

				M. Boodhwani, Y. Nakai, S. Mieno, P. Voisine, C. Bianchi, E. G. Araujo, J. Feng, K. Michael, J. Li, and F. W. Sellke Hypercholesterolemia Impairs the Myocardial Angiogenic Response in a Swine Model of Chronic Ischemia: Role of Endostatin and Oxidative Stress Ann. Thorac. Surg., February 1, 2006; 81(2): 634 - 641. [Abstract] [Full Text] [PDF]

				X. Zeng, J. Chen, Y. I. Miller, K. Javaherian, and K. S. Moulton Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis J. Lipid Res., September 1, 2005; 46(9): 1849 - 1859. [Abstract] [Full Text] [PDF]

				A. G. Marneros and B. R. Olsen Physiological role of collagen XVIII and endostatin FASEB J, May 1, 2005; 19(7): 716 - 728. [Abstract] [Full Text] [PDF]