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.elastic fibers ͉ extracellular matrix ͉ neointima ͉ elastin V ascular obstructive abnormalities, such as atherosclerosis and restenosis after percutaneous coronary intervention, are triggered by damage to the vessel wall, initiating a series of biological responses, including up-regulation of adhesion molecules, recruitment of inflammatory cells, secretion of cytokines, and activation of smooth muscle cells (SMCs). Activated SMCs secrete growth factors, extracellular matrix proteins, and matrix proteases, thereby altering the microenvironment of the injured vessel wall. Much attention has focused on the signaling pathways responsible for the proliferation and migration of SMCs associated with vascular obstruction, but relatively little is known of the potential contributions of extracellular matrix proteins to these processes (reviewed in ref. 1).Structural changes of the vessel wall induced by mechanical force or enzymatic digestion also influence the development of vascular obstructive disease (2, 3). The elastic lamina plays a critical role in maintaining the integrity of the vessel wall. Rupture of the external elastic lamina (EEL) is a more potent stimulus for neointima formation than injury involving the internal elastic lamina (IEL) alone after coronary artery stent-induced injury (4). In addition, exposure of the adventitia to the blood lumen by disruption of the EEL during percutaneous angioplasty increases the activation of adventitial myofibroblasts, leading to adventitial fibrosis that eventually constricts the vessel wall (5).The perception of the elastic lamina (or elastic fibers) as the sole structural component of the vessel wall was recently challenged by the view that elastic fibers actively modulate intercellular signaling. Elastin (eln), a major component of the elastic fibers in the arterial wall, inhibits proliferation of SMCs (6). Eln is secreted as a tropoelastin monomer and subsequently undergoes cross-linking t...

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Abstract-Transgenic mice overexpressing the calcium binding protein, S100A4/Mts1, occasionally develop severe pulmonary vascular obstructive disease. To understand what underlies this propensity, we compared the pulmonary vascular hemodynamic and structural features of S100A4/Mts1 with control C57Bl/6 mice at baseline, following a 2-week exposure to chronic hypoxia, and after 1 and 3 months "recovery" in room air. S100A4/Mts1 mice had greater right ventricular systolic pressure and right ventricular hypertrophy at baseline, which increased further with chronic hypoxia and was sustained after 3 months "recovery" in room air. These findings correlated with a heightened response to acute hypoxia and failure to vasodilate with nitric oxide or oxygen. S100A4/Mts1 mice, when compared with C57Bl/6 mice, also had impaired cardiac function judged by reduced ventricular elastance and decreased cardiac output. Despite higher right ventricular systolic pressures with chronic hypoxia, S100A4/Mts1 mice did not develop more severe PVD, but in contrast to C57Bl/6 mice, these features did not regress on return to room air. Microarray analysis of lung tissue identified a number of genes differentially upregulated in S100A4/Mts1 versus control mice. One of these, fibulin-5, is a matrix component necessary for normal elastin fiber assembly. Fibulin-5 was localized to pulmonary arteries and associated with thickened elastic laminae. This feature could underlie attenuation of pulmonary vascular changes in response to elevated pressure, as well as impaired reversibility. Key Words: elastin Ⅲ fibulin-5 Ⅲ hypoxia Ⅲ mouse Ⅲ pulmonary hypertension Ⅲ smooth muscle cells Ⅲ S100 proteins Ⅲ vascular smooth muscle cells Ⅲ vascular disease F amilial idiopathic pulmonary arterial hypertension (PAH) is associated with mutations in bone morphogenetic receptor II (BMPR-II), but the inheritance pattern is that of a dominant gene with low penetrance, in that only Ϸ20% of affected family members develop the disease. 1,2 This coupled to the fact that genetically engineered mice with abnormalities in BMPR-II have pulmonary hypertension but fail to reproduce the pathology seen in patients with pulmonary vascular obstructive disease (PVD) 3,4 indicates that multiple genetic and environmental cofactors may be necessary for the disease to develop. A potential modifier gene is the calciumbinding protein, S100A4/Mts1, because a small subpopulation (Ϸ5%) of transgenic mice Ͼ1 year of age, that overexpress S100A4/Mts1, develops PVD. 5 Furthermore, heightened expression of S100A4/Mts1 is observed in the neointima and adventitia of occlusive and early plexiform lesions in patients with a congenital heart defect or idiopathic PAH. 5 S100A4/Mts1 is induced in malignant metastatic breast cancer 6 and although its intracellular properties have been implicated in the motility of cancer cells, 7 it is also secreted and can stimulate angiogenesis. 8 Moreover, recombinant S100A4/Mts1 promotes proliferation and migration of cultured pulmonary artery (PA) SMC. 8a Although ...

Background and purpose Charcot–Marie–Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. Methods Individuals with FBLN5‐associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients’ visits at our centres or primary care sites. Results Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. Conclusions Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work‐up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5‐associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.