Phenotypic Alteration of Vascular Smooth Muscle Cells Precedes Elastolysis in a Mouse Model of Marfan Syndrome

Abstract

Abstract-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 suggested that a deficiency of microfibrils causes failure of elastic fiber assembly during late fetal development. Mice homozygous for a targeted hypomorphic allele (mgR) of Fbn1 revealed a predictable sequence of abnormalities in the vessel wall including elastic fiber calcification, excessive deposition of matrix elements, elastolysis, and intimal hyperplasia. Here we describe previously unrecognized concordant findings in elastic vessels from patients with Marfan syndrome. Furthermore, ultrastructural analysis of mgR mice revealed cellular events that initiate destructive changes. The first detectable abnormality was an unusually smooth surface of elastic laminae, manifesting the loss of cell attachments that are normally mediated by fibrillin-1. Adjacent cells adopted alteration in their expression profile accompanied by morphological changes but retained expression of vascular smooth muscle cell markers. The abnormal synthetic repertoire of these morphologically abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediator of elastolysis. Ultimately, cell processes associated with zones of elastic fiber thinning and fragmentation. These data suggest that the loss of cell attachments signals a nonproductive program to synthesize and remodel an elastic matrix. This refined understanding of the pathogenesis of vascular disease in Marfan syndrome will facilitate the development of therapeutic strategies. (Circ Res. 2001;88:37-43.)

Structural and Genetic Bases of Arterial Stiffness

“…43 Electron microscopy showed that elastic laminae had an unusually smooth surface and lacked the cell attachments normally mediated by FBN1. 44 Bunton et al 44 suggested that the loss of cell attachments triggers signaling initiating a nonproductive program for the synthesis and remodeling of an elastic matrix. Thus, FBN1 appears to be a key element in the normal spatial organization of the arterial wall, ensuring adequate loading of elastic components, thereby maintaining physiological arterial stiffness.…”

Fibrillin‐rich microfibrils: Structural determinants of morphogenetic and homeostatic events

“…The so-called mgR mouse produces structurally normal fibrillin-1 protein at $15% of the normal level and in homozygosity replicates the adult lethal form of MFS (Pereira et al, 1999). Ruptured aortic aneurysm in mgR/mgR mice is preceded by a series of secondary events that include medial calcification, ECM accumulation, intimal hyperplasia, and adventitial inflammation (Pereira et al, 1999;Bunton et al, 2001). Overall, these secondary events suggested the activation of an unproductive tissue repair response, which results in intense elastolysis and consequent exacerbation of the structural collapse of the aortic wall (Pereira et al, 1999;Bunton et al, 2001).…”

“…Ruptured aortic aneurysm in mgR/mgR mice is preceded by a series of secondary events that include medial calcification, ECM accumulation, intimal hyperplasia, and adventitial inflammation (Pereira et al, 1999;Bunton et al, 2001). Overall, these secondary events suggested the activation of an unproductive tissue repair response, which results in intense elastolysis and consequent exacerbation of the structural collapse of the aortic wall (Pereira et al, 1999;Bunton et al, 2001). As already stated, subsequent studies of other fibrillin-1 mutant mice implicated enhanced TGF-b activity in initiating and/or maintaining pathogenic events in this mouse model of MFS.…”

“…First described in 1896 by AntoineBernard Marfan (Marfan, 1896), MFS was later recognized by Victor McKusick as the founding member of the so-called heritable disorders of the connective tissue, which he predicted to be the result of structural or metabolic dysfunctions of ECM proteins (McKusick, 1955). Aside from confirming McKusick's prediction, the demonstration that fibrillin-1 mutations cause MFS provided a logical explanation for disease pathogenesis based on the concept that they would lead to the formation of a structurally impaired connective tissue by interfering with normal microfibril assembly (Aoyama et al, 1994;Eldadah et al, 1995).The recent creation of mouse models of MFS has questioned the original idea that MFS abnormalities are solely accounted for by loss of tissue integrity in that they have implicated perturbation of TGF-b signaling in the progression of the disease (Pereira et al, 1999;Bunton et al, 2001;Neptune et al, 2003;Ng et al, 2004). This paradigm switch has already paved the way for a new drug-based strategy that is based on TGF-b antagonism (Habashi et al, 2006).…”

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

“…19) In addition, inflammatory T lymphocytes and macrophages reportedly infiltrate aortic media and adventitia, and those numbers were negatively correlated with patient ages at referral for prophylactic surgical repair, suggesting that inflammation might affect disease progression. 20,21) Dietz and his colleagues performed the most extensive mechanistic studies of these diseases, and identified FBN1 as a causative gene in 1991, 4) with FBN1 mutations accounting for > 60% of MFS patients.…”