© 2001 American Heart Association, Inc.
Molecular Medicine |
Phenotypic Alteration of Vascular Smooth Muscle Cells Precedes Elastolysis in a Mouse Model of Marfan Syndrome
From the Departments of Comparative Medicine and Pathology (T.E.B.), Institute for Genetic Medicine (N.J.B., L.M., H.C.D.), and Howard Hughes Medical Institute (H.C.D.), Johns Hopkins University School of Medicine, Baltimore, Md; and Brookdale Center for Developmental and Molecular Biology (B.G., F.R.), Mount Sinai School of Medicine, New York, NY. Dr Bunton’s present affiliation is Department of Safety Assessment, DuPont Pharmaceuticals Co, Newark, Del.
Correspondence to Harry C. Dietz, Institute for Genetic Medicine, Johns Hopkins Hospital, Ross 858, 720 Rutland Ave, Baltimore, MD 21205. E-mail hdietz{at}jhmi.edu
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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.
Key Words: Marfan syndrome • fibrillin • microfibril • elastin • aneurysm
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Introduction |
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Marfan syndrome (MFS) is a systemic disorder of connective tissue with a prevalence of
1:10 000 individuals.1
The disorder has pleiotropic manifestations that include dislocation of
the ocular lens, long bone overgrowth, and dilatation of the proximal
aorta that predisposes to aortic dissection and rupture. MFS shows
dominant inheritance and complete penetrance, but considerable clinical
variation is seen both within and between affected
families.2 Vascular disease in MFS is characterized by elastic matrix abnormalities in the medial layer of the aortic wall, including fragmentation and disorganization of elastic fibers, a generalized loss of elastin content, and the accumulation of amorphous matrix components.3 4 5 6 7 8 The elastin gene was excluded as the site of primary defect, and in 1991, a positional candidate approach demonstrated that mutations that cause MFS occur in the FBN1 gene that encodes fibrillin-1.9 10 11 12 This 350-kDa glycoprotein is the major structural constituent of 10-nm extracellular microfibrils.13
Microfibrils are found at the margins of maturing elastic fibers during embryogenesis. This temporal and spatial association contributed to the hypothesis that fibrillin-1 and microfibrils play essential roles in the regulated deposition of tropoelastin molecules during development.14 15 16 In this scenario, the deficiency in elastic fiber abundance and architecture that is observed in mature vascular lesions is predominantly due to a primary failure of elastogenesis.
This view was challenged by the analysis of mice
homozygous for a targeted Fbn1 allele that expresses very low levels of
a centrally deleted monomer
(mg
)17 or for a
hypomorphic allele that expresses normal monomer at a level
approximating 15% of normal
(mgR).18 Homozygous mg
mice documented that minimal residual microfibrillar function is
sufficient to support the deposition of an organized elastic matrix
that shows secondary
deterioration.17 This
finding underscored the prominent role of fibrillin-1 in the
homeostasis of established elastic fibers. Early death of these
animals, however, precluded full appreciation of the pathogenetic
sequence that leads to aneurysm formation. The longer life-span of mgR
homozygotes allowed the observation of additional events, including
focal calcification of intact elastic laminae, intimal hyperplasia,
excessive and disorganized synthesis and secretion of matrix components
(collagens, proteoglycans, and elastin) throughout the vessel wall, and
ultimate recruitment of inflammatory cells with associated
elastolysis.17
In the present study, we use ultrastructural analysis to define events that precede and initiate destructive changes in the aortic media of fibrillin-1–deficient mice. Changes in the architecture of elastic laminae were associated with phenotypic alterations in flanking vascular smooth muscle cells (VSMCs), including the initiation of an abnormal synthetic program. In addition to matrix components, these cells elaborate mediators of elastolysis that contribute to the structural collapse of the vessel wall. These data provide novel insight into the pathogenesis of genetically predisposed ascending aortic aneurysm that may have relevance for acquired forms of disease. They also suggest new opportunities for the development of rational therapeutic strategies.
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Materials and Methods |
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Histology and Immunohistochemistry
Mice were killed with an inhalation overdose of methoxyflurane (Metofane; Schering-Plough). Tissues were fixed by immersion in Bouin’s fixative, routinely processed for paraffin embedment, and sectioned at 5.0 µm. Tissue sections were stained with hematoxylin and eosin (H&E), alizarin red for calcium, Verhoeff-van Gieson for elastic tissue, and trichrome for collagen. Sections were processed for immunohistochemistry with mouse monoclonal antibodies directed against matrix metalloproteinase type 9 (MMP9; 1:1000 dilution; Santa Cruz Biotechnology, Inc), smooth muscle actin, and vimentin (both 1:500 dilution; BioGenex) as previously described.18 Biotinylated horse anti-mouse IgG (1:500 dilution; Vector Laboratories) was used as secondary antibody, and staining was achieved with streptavidin-conjugated horseradish peroxidase (Jackson ImmunoResearch) and aminoethycarbazole (Sigma Chemical Co).
In Situ Hybridization
Four wild-type and 4 homozygous mgR mice from 10 to
14 months of age were killed as described here, and the aorta was
perfused in situ with 4% cold paraformaldehyde in PBS before resection
at the level of the diaphragm. After 24 hours of fixation, 5.0-µm
paraffin sections of aorta were prepared. A mouse tropoelastin cDNA
clone was obtained from Genome Systems. For the antisense probe, the
plasmid was linearized with
EcoRI and transcribed with
T3 RNA polymerase. For the sense control, the plasmid was linearized
with NotI and
transcribed with T7 RNA polymerase. In situ hybridization analysis was
performed with 35S-labeled
riboprobes.19 Adjacent
sections were stained with H&E.
Electron Microscopy
Four mgR homozygote and 4 wild-type mice ranging from
11 to 15 months of age were killed as described here. The chest was
opened, and the heart was perfused in situ with 3.0% cold
glutaraldehyde in 0.1 mol/L sodium cacodylate buffer. The heart and
aorta to the level of the diaphragm were dissected from the lungs,
thymus, and other mediastinal tissues and fixed for 48 hours. The
aortic arch and descending aorta were isolated and cut into cross and
longitudinal sections, postfixed with 1.0% osmium tetroxide in 0.1
mol/L sodium cacodylate buffer, rinsed, and immersed in 2.0% tannic
acid in 0.1 mol/L sodium cacodylate for 1 hour to enhance the contrast
of elastic
fibers.20 21 22
Tissues were then dehydrated in a graded series of alcohols and
embedded in Araldite 502. One-micron sections were stained with
toluidine blue. Thin sections on copper grids were stained with uranyl
acetate and lead citrate and examined with a Phillips CM12 electron
microscope.
Review of Archived Pathological
Specimens
The records of patients with MFS who underwent an
autopsy between 1954 and the present were identified from the autopsy
archives of Johns Hopkins University Hospital. Original slides were
examined to determine vascular architecture and the distribution of
calcification in vessels. When paraffin blocks were available,
additional sections were cut and stained with alizarin red to confirm
the presence of calcium in the elastic
media.
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Results |
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Vascular Phenotype in MFS Patients
Existing mouse models and MFS patients have partial but not complete loss of microfibrillar function due to different molecular mechanisms. It seemed likely that homozygosity for loss-of-function alleles in mice would have a similar consequence to heterozygosity for a dominant-negative allele, as seen in the human condition. To validate this hypothesis, the aorta and other large muscular arteries from 7 patients diagnosed with MFS and ascending aortic aneurysm were examined to compare the vascular phenotype with that seen in mice homozygous for the targeted mgR allele. The average age at death was 33 years (range 14 to 49 years). All patients showed calcium deposition in multiple vessels, including the aorta and subclavian, pulmonary, renal, iliac, and splenic arteries (Figures 1a
and 1b). In the aorta, calcification affected the
internal elastic lamina (IEL) and residual elastic fibers in the media.
In all other vessels, there were discontinuous linear calcium deposits
that involved the IEL. In addition, calcification was associated with
intimal hyperplasia and excessive deposition of collagen in the iliac,
subclavian, and splenic arteries
(Figures 1b and 1c). Although such changes are common after
the fifth decade of life in the normal population, the distribution and
severity of findings in these patients with MFS were distinctly
atypical for children or young
adults.23
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Ultrastructure of Aorta in
Fibrillin-1–Deficient Mice
With high-resolution light microscopy, vascular lesions
in mgR/mgR mice were characterized by random discontinuities in elastic
laminae in both the aortic arch and descending aorta. Centrally located
fibers were primarily affected with relative sparing of the IEL and
external elastic laminae (EEL)
(Figures 2a and 2d).
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Ultrastructural analysis showed that the borders of aortic
elastic laminae in control animals were highly irregular. Surface
projections on elastic laminae connected to cytoplasmic processes of
VSMCs through an intermediate structure composed of microfibrils
(Figures 2b
and 2c).20 21 22
In contrast, the elastic laminae in mice underexpressing fibrillin-1
were remarkably smooth with direct abutment of VSMC processes
(Figures 2e and 2f). Although present in mgR/mgR mice, normal
junctions composed of microfibrillar bundles were significantly reduced
in number. These changes were seen in all animals that were examined
and in both lesional and nonlesional aortas. The cells demonstrated an
increased surface area due to an increased number and complexity of
cytoplasmic extensions
(Figures 2e and 3). Synthetic organelles were prominent,
including the Golgi apparatus, endoplasmic reticulum, and cytoplasmic
vacuoles with homogeneous osmiophilic content
(Figure 3c). Nascent matrix elements, including amorphous
elastin and bundles of collagen, were observed in cytoplasmic bays.
Projections of VSMCs were often associated with regions of thinning or
breach of elastic laminae with fragments of amorphous elastin in the
local environment
(Figures 3b and 3c). Calcification was commonly seen at the
sites of breaks in elastic laminae but could also be seen in the core
of intact elastic fibers
(Figure 3d). VSMCs extended through gaps where elastic
laminae were thinned to the point of disruption. Fragmentation of the
IEL was associated with degenerative changes in endothelial cells and
the presence of inflammatory cells in the media (data not shown).
Disruptions in the EEL were associated with the accumulation of
inflammatory cells and fibroblasts in the adjacent adventitia
(Figure 3e).
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Synthetic Profile of VSMCs in
Fibrillin-1–Deficient Mice
Ultrastructural changes in the aortic media of both
lesional and nonlesional aortas in mgR/mgR mice revealed a dramatic
increase in synthetic organelles of VSMCs in association with dramatic
thickening of the aortic media that manifests excessive accumulation of
matrix elements, including collagen, proteoglycan, and elastin.
Although the accumulation of extracellular matrix is inherent to
neointimal formation, these findings occurred when the cells remained
within the confines of intact elastic laminae. To illustrate that these
findings were attributable, at least in part, to an abnormal synthetic
state of VSMCs, we used in situ hybridization to assess expression of
tropoelastin message. The elastin gene is normally not robustly
transcribed in VSMCs within a mature aortic media. As seen in
Figure 4, we observed a dramatic upregulation of elastin
mRNA in homozygous mgR animals.
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VSMC processes were found closely opposed to sites of
elastic fiber destruction in homozygous mgR mice. To investigate the
chemical mediators of elastolysis, immunohistochemical staining was
performed for MMP9. This enzyme is expressed by fetal VSMCs during
matrix assembly and
remodeling24 25 26
and can degrade elastin and fibrillin-1, among other matrix elements.
VSMC expression of MMP9 was uniquely seen within the aortic wall of
fibrillin-1–deficient mice
(Figure 5). Immunoreactivity was observed within early
lesions, before overt elastolysis or infiltration of inflammatory cells
into the media
(Figures 5b and 5c). The local expression level of MMP9 within
the aortic media generally correlated with the extent of loss of
elastin content and elastic fiber architecture during lesional
maturation
(Figures 5b and 5c). In late lesions, inflammation was first
evident at the adventitial border, often in association with
infiltration into the media, intense expression of MMP9, and structural
collapse of the vessel wall
(Figure 5d).
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Differentiation Status of VSMCs in
Fibrillin-1–Deficient Mice
Changes in the synthetic repertoire of VSMCs can occur
coincident with changes in cellular differentiation status, as observed
in neointima formation. Atypically, however, a dramatic upregulation of
matrix production was evident in mgR/mgR mice before overt elastic
fiber destruction or migration of VSMCs. Ongoing expression of smooth
muscle actin and the absence of upregulation of vimentin within the
media of homozygous-targeted animals served as positive markers of
maintenance of cellular differentiation
(Figure 6).
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Discussion |
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Despite the major contribution of aortic aneurysm to mortality rates in industrialized countries, its cause and pathogenesis remain poorly understood. A favored model suggests that aneurysm results from an imbalance between proteolytic and homeostatic mechanisms within the vessel wall. A primary increase in the local or systemic activity of MMPs, serine proteases, or cysteine proteases has been implicated.27 28 29 30 31 32 33 34 35 Alternatively, others have proposed a deficiency of protease inhibitors, including tissue inhibitor of MMPs,
1-antitrypsin, or cystatin
C.28 34 35 36 37 38 39 40
Although it is likely that these observations are relevant to the
progression of aortic aneurysm, the events that initiate vessel wall
destruction remain entirely unclear. To date, major genetic determinants of aortic aneurysm have been defined only for selected heritable disorders of connective tissue. Foremost among these is the MFS that is caused by mutations in the gene that encodes fibrillin-1.12 Mouse models of fibrillin-1 deficiency suggest that aneurysm does not result from primary failure of elastogenesis.17 18 Rather, secondary events have been defined, including elastic fiber calcification, intimal hyperplasia, and the recruitment of an inflammatory infiltrate.18 In that similar histopathological findings had not been described in patient surgical or autopsy specimens, their relevance to the human condition remained suspect. We reasoned that most pathological studies had focused on end-stage lesions of the proximal aorta and initiated a comprehensive review of archived specimens from young individuals with MFS. Elastic fiber calcification, intimal hyperplasia, and abnormal deposition of matrix elements were observed widely in medium-to-large elastic arteries. Takebayashi et al41 42 had previously reported an odd appearance of fragmented elastic laminae in the media of the aorta and peripheral arteries in patients with MFS. This "osmiophilic elastolysis" was characterized by the accumulation of an electron-dense and granular material on the surface of and within elastic fibers.42 Although attributed to the accumulation of a peculiar breakdown product of elastin, it is clear in retrospect that the authors were actually observing diffuse calcification of elastic structures. These changes occurred in children without an apparent correlation between distribution or severity and the age of the individual. The presence of calcification in vessels that are not predisposed to dilatation in MFS suggests that it is neither sufficient to initiate aneurysm formation nor a marker of sufficient damage to obligate this process. The event that promotes calcification remains unknown. It is possible that the surface of elastic laminae devoid of microfibrillar connections, with or without destructive changes, is simply more susceptible to calcium deposition. Alternatively, smooth muscle cells that have lost matrix attachments may fail to secrete molecules that provide active protection against local calcification, such as osteoprotegerin or matrix GLA protein.43 44 There are no data that suggest systemic dysregulation of calcium homeostasis in MFS.
Prior ultrastructural analysis of the developing mouse aorta
demonstrated that elastic laminae connect to adjacent endothelial and
VSMCs through an intermediate structure that immunoreacts with
antibodies directed against
fibrillin-1.20 21 22
It has also been shown that the RGD sequence of fibrillin-1 can support
cellular adhesion via integrin
Vß3.45 46 47
These interactions have been proposed to maintain the architecture of
the vessel wall through cell anchorage and to coordinate contractile
and elastic
tensions.20 21
Both homozygous mgR mice and MFS patients have partial, but not
complete, loss of microfibrillar function. The ultrastuctural analysis
reported here provides the first demonstration that a normal complement
of fibrillin-1 is essential for the structural integrity of connecting
filaments and that fibrillin-2 or other connective tissue elements
cannot compensate for its deficiency. Hemodynamic stress or other
environmental factors may promote progressive loss of the scant
connecting filaments that are observed in nonlesional tissue. Loss of
physical interactions, and hence signals that specify context,
associates with a synthetic response in VSMCs, as evidenced by
morphological changes and upregulated synthesis of multiple matrix
elements
(Figure 7). These phenotypic changes begin in cells within
the aortic media that remain flanked by intact elastic laminae but
become more pronounced when elastic fiber fragmentation occurs. It
remains unclear whether the cells are sensing and responding to a loss
of connection, local damage, perturbation in the functional properties
of the vessel wall, or some combination thereof. The aortic wall is
abnormally stiff in
MFS.48 49
Interestingly, the thickened aorta of spontaneously hypertensive rats
shows normal distensibility and an increased density of connections
between VSMCs and the elastic
matrix.50 Taken together,
these data suggest an inverse relationship between the quantity or
quality of these connections and vessel wall compliance.
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Immunoreactivity for MMPs, particularly types 2 and 9, had
previously been observed at the periphery of mature vascular lesions in
patients with MFS.51 This
temporal and spatial pattern of MMP expression precluded distinction
between a primary event in pathogenesis and a secondary response or
marker of end-stage aortic disease. Here, we show that in addition to
multiple matrix components, VSMCs in fibrillin-1–deficient mice
elaborate mediators of elastolysis including MMP9 in early vascular
lesions, before overt elastic fiber destruction
(Figure 7). As a general rule, the local intensity of MMP9
expression correlated inversely with elastic fiber content and
integrity. The conclusion that the elastolytic enzymes elaborated by
VSMCs initiate elastolysis is supported by the ultrastructural
demonstration of elastic fiber thinning and fragmentation in
association with alterations in the morphology and synthetic profile of
neighboring cells. These elastic fiber changes are typical of those
observed with experimentally induced elastolysis after the
administration of exogenous
elastase.52 Later breach of
the IEL and/or EEL allows infiltration of inflammatory cells into the
media, resulting in intense elastolysis that contributes to the
structural collapse of the aortic
wall.18 Although intense
inflammatory changes are not routinely observed in patients with MFS,
they may be either focal or transient. It is interesting to note that
the prominent role of inflammation in the pathogenesis of cerebral,
abdominal aortic, and atherosclerotic aneurysms has only recently been
appreciated.29 30 53 54
Alternatively, the elastolytic enzymes elaborated by VSMCs alone may be
sufficient to promote aneurysm formation in MFS.
The study of genetically defined abnormalities of the elastic matrix in mice has resulted in an enhanced understanding of multiple disease processes. Elastin has been proposed to influence the phenotype of VSMCs in developing blood vessels and myofibroblasts in the developing lung.55 56 57 To a large extent, this is based on an association between the perturbation of elastin expression and abnormalities of cellular composition and behavior. The abnormal proliferative and synthetic state of VSMCs in supravalvar aortic stenosis (SVAS) patients hemizygous for the elastin gene or elastin knockout mice may manifest a loss of matrix cellular signaling,57 58 as we propose in fibrillin-1–deficient mice. Alternatively, in SVAS, these phenotypic changes may simply reflect the loss of a structural constraint to cellular proliferation normally imposed by neighboring elastic laminae.
Selected VSMC and connective tissue abnormalities observed in SVAS and MFS are also seen in many common disease processes, including nonsyndromic aortic aneurysm, hypertension, and maturation of atheromatous lesions.59 60 61 62 Indeed, the paradigm of limited elastic fiber degradation progressing to intense elastolysis in association with inflammatory infiltration of the vessel wall and increased expression of MMPs is emerging as a common theme in the pathogenesis of aneurysm.29 30 34 63 64 Intimal hyperplasia, vascular calcification, and elastolysis are also components of the normal aging process.23 65 66 It is therefore interesting to speculate that a primary or acquired deficiency of cell-elastic matrix connections contributes to all of these processes. These data suggest that therapeutic strategies aimed at modulation of cellular phenotype and/or inhibition of protease activity may hold promise to preclude or delay the development of clinically manifest aortic disease due to a wide variety of genetic and environmental predispositions. It may be particularly informative to determine whether the introduction of targeted deletions for the genes encoding MMPs 2, 9, and/or 12 or overexpression of tissue inhibitors of metalloproteinases in fibrillin-1–deficient mice has the ability to abbreviate or abrogate vessel wall disease.37 64
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Acknowledgments |
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This work was supported by the Howard Hughes Medical Institute, National Institutes of Health (grants AR-41135 and AR-42044), National Marfan Foundation, Smilow Foundation, Dana and Albert Broccoli Center for Aortic Diseases, and Dr Amy and James Elster Research Fund.
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Footnotes |
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Original received June 26, 2000; revision received October 23, 2000; accepted October 30, 2000.
This manuscript was sent to Peter Libby, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
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