Spencer Jeffrey A, Hacker Shelby L, Davis Elaine C, Mecham Robert P, Knutsen Russ H, Li Dean Y, Gerard Robert D, Richardson James A, Olson Eric N, Yanagisawa Hiromi
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2946-51. doi: 10.1073/pnas.0500058102. Epub 2005 Feb 14.
Fibulin (fbln)-5 is an elastin-binding protein required for assembly and organization of elastic fibers. To examine the potential role of fbln-5 in vascular remodeling and neointima formation, we induced vascular injury by carotid artery ligation in fbln-5(-/-) mice. Mutant mice displayed an exaggerated vascular remodeling response that was accompanied by severe neointima formation with thickened adventitia. These abnormalities were not observed in elastin(+/-) mice that exhibited a comparable reduction of vessel extensibility to fbln-5(-/-) mice. Thus, the severe remodeling response could not be attributed to altered extensibility of the vessel wall alone. Vascular smooth muscle cells cultured from fbln-5(-/-) mice displayed enhanced proliferative and migratory responses to mitogenic stimulation relative to wild-type cells, and these responses were inhibited by overexpression of fbln-5. These findings demonstrate the importance of the elastic laminae in vascular injury, and reveal an unexpected role of fbln-5 as an inhibitor of vascular smooth muscle cell proliferation and migration.
纤维连接蛋白（fbln）-5是一种弹性纤维组装和组织所需的弹性蛋白结合蛋白。为了研究fbln-5在血管重塑和新生内膜形成中的潜在作用，我们通过结扎fbln-5基因敲除（-/-）小鼠的颈动脉来诱导血管损伤。突变小鼠表现出过度的血管重塑反应，伴有严重的新生内膜形成和外膜增厚。在弹性蛋白杂合（+/-）小鼠中未观察到这些异常，这些小鼠的血管伸展性降低程度与fbln-5基因敲除（-/-）小鼠相当。因此，严重的重塑反应不能仅归因于血管壁伸展性的改变。与野生型细胞相比，从fbln-5基因敲除（-/-）小鼠培养的血管平滑肌细胞对有丝分裂原刺激表现出增强的增殖和迁移反应，并且这些反应被fbln-5的过表达所抑制。这些发现证明了弹性层在血管损伤中的重要性，并揭示了fbln-5作为血管平滑肌细胞增殖和迁移抑制剂的意外作用。
