title: Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis.
abstract: Circulating inflammatory mediators including complement activation products participate in the pathogenesis of cardiovascular diseases. As such, previous reports demonstrating the presence of complement proteins within atherosclerotic plaque and on the luminal surface would be anticipated. In contrast, we have recently made the unexpected observation that complement proteins also deposit along the external elastic lamina of mouse aortas in the absence of luminal deposition or plaque development. This suggests that complement activation may play a critical role in the pathogenesis of vascular stiffness and atherosclerosis through a mechanism initiated within the adventitia rather than on the endothelial surface. This hypothesis was tested in the current study by ultrastructural identification of the C3- and C4-binding targets within the adventitia of the mouse aorta. The results demonstrate extensive binding of C3 and C4 to both collagen and elastin fibers within the adventitia in both ApoE(-/-) and C57Bl/6J control mice, as well as the presence of C3 and C4 within perivascular adipose tissue. These observations suggest a potential "outside-in" mechanism of vascular stiffness during which perivascular adipose may produce C3 and C4 that bind to collagen and elastin fibers within the adventitia through covalent thiolester bonds, leading to increased vascular stiffness.
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Shields
authors.forename: Donna
authors.initials: D
authors.lastname: Stolz
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ahearn
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001013:Aorta, Thoracic / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry*; D003176:Complement C3 / Q000737:chemistry*; D003181:Complement C4 / Q000737:chemistry*; D004549:Elastin / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D011485:Protein Binding
chemical_list: D001057:Apolipoproteins E; D003176:Complement C3; D003181:Complement C4; D003094:Collagen; D004549:Elastin