Phenotypic alteration of vascular smooth muscle cells precedes elastolysisin a mouse model of Marfan syndrome

Marfan syndrome is associated with early death due to aortic aneurysm. The condition is caused by mutations in the gene (FBN1) encoding fibrillin-1, a major constituent of extracellular microfibrils. Prior observations sugges ted that a deficiency of microfibrils causes failure of elastic fiber assem bly during late fetal development. Mice homozygous for a targeted hypomorph ic allele (mgR) of Fbn1 revealed a predictable sequence of abnormalities in the vessel wall including elastic fiber calcification, excessive depositio n of matrix elements, elastolysis, and intimal hyperplasia. Here we describ e previously unrecognized concordant findings in elastic vessels from patie nts with Marfan syndrome. Furthermore, ultrastructural analysis of mgR mice revealed cellular events that initiate destructive changes. The first dete ctable abnormality was an unusually smooth surface of elastic laminae, mani festing the loss of cell attachments that are normally mediated by fibrilli n-1, Adjacent cells adopted alteration in their expression profile accompan ied by morphological changes but retained expression of vascular smooth mus cle cell markers. The abnormal synthetic repertoire of these morphologicall y abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediat or of elastolysis. Ultimately, cell processes associated with zones of elas tic fiber thinning and fragmentation. These data suggest that the loss of c ell attachments signals a nonproductive program to synthesize and remodel a n elastic matrix. This refined understanding of the pathogenesis of vascula r disease in Marfan syndrome will facilitate the development of therapeutic strategies.