Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice

Fibrillin-1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibres, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin-1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular ageing has raised the possibility that fibrillin-1 deficiency could also contribute to late-onset pathology of vascular remodelling. To address this question, we examined cardiovascular function in 3-week-old, 6-month-old, and 24-month-old mice that are heterozygous for a hypomorphic structural mutation of fibrillin-1 (Fbn1{+/mgΔ} mice). Our results indicate that Fbn1{+/mgΔ} mice, particularly those that are 24 months old, are slightly more hypotensive than wild-type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in ageing Fbn1{+/mgΔ}$ mice than in the wild-type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of Fbn1{+/mgΔ} mice, which were correlated with an increase in aortic stiffness, a decrease in vasoreactivity, altered expression of elastic fibre-related genes, including fibrillin-1 and elastin, and a decrease in the relative ratio between tissue elastin and collagen. Collectively, our findings suggest that the heterozygous mgΔ mutation accelerates some aspects of vascular ageing and eventually leads to aortic manifestations resembling those of Marfan syndrome. Importantly, our data also indicate that vascular abnormalities in Fbn1{+/mgΔ} mice are opposite to those induced by elastin haploinsufficiency during ageing that affect blood pressure, vascular dimensions, and number of elastic lamellae.     

Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBNl, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uninformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible. © 1994 Wiley-Liss, Inc.     

Stretching modulates oxytalan fibers in human periodontal ligament cells

Background and Objective:  Oxytalan fibers, as well as collagen fibers, are the structural components of periodontal ligaments. Periodontal ligaments are continuously exposed to various functional forces. However, the behavior of oxytalan fibers under mechanical strain has not been investigated. We hypothesized that strain would alter the amount and appearance of oxytalan fibers in terms of positivity for their major components, fibrillin-1 and fibrillin-2.
Material and Methods:  We subjected periodontal ligament fibroblasts to stretching strain to examine the effects on their formation of oxytalan fibers in cell/matrix layers.
Results:  Stretching increased the levels of fibrillin-1 and fibrillin-2 by 25% relative to the control, but did not affect the gene expression level of either type of fibrillin. Immunofluorescence and immunogold electron microscopy analysis revealed that bundles of oxytalan fibers became thicker under stretching conditions.
Conclusion:  These results suggest that tension strain functionally regulates microfibril assembly in periodontal ligament fibroblasts and thus may contribute to the homeostasis of oxytalan fibers in periodontal ligaments.     

The use of retinoids in the treatment of photoaging

Photoaging describes the clinical and histologic consequences of chronic sun exposure, the key features of which--wrinkles and mottled hyperpigmentation--are frequently and erroneously attributed to the aging process. Although a number of surgical procedures can improve the clinical appearance of photoaged skin, the only medical therapy with proved benefit derived from randomized clinical trial evidence is the use of topical retinoids, particularly tretinoin, isotretinoin, and tazarotene. Retinoids are capable not only of repairing photoaged skin at both the clinical and biochemical levels but their use may prevent photoaging. There is in addition emerging evidence that topical retinoids could be beneficial in the treatment of intrinsically aged skin.     

Repair of photoaged dermal matrix by topical application of a cosmetic 'antiageing' product

BACKGROUND: Photoaged skin is characterized by coarse and fine wrinkles. The mechanism of wrinkle formation appears to involve changes to components of the dermal extracellular matrix. Topical treatment with all-trans retinoic acid (RA) can repair photoaged dermal matrix; this is regarded as the 'gold standard' against which repair agents are judged. To date, little is known regarding the ability of over-the-counter 'antiageing' products to repair photoaged skin. OBJECTIVES: We used a modified occluded patch test to ascertain whether topical applications of cosmetic 'antiageing' products are able to repair photoaged human skin. METHODS: Commercially available test products [basic moisturizer, 'antiageing' cream containing different active complex levels (6% active: lipopentapeptide, white lupin peptides, antioxidants, retinyl palmitate; 2% active: lipopentapeptide, white lupin peptides, antioxidants)] were applied under occlusion for 12 days prior to biopsy and histological assessment in photoaged volunteers (n=9). RA was used as a positive control. RESULTS: In agreement with previous studies, the patch-test study revealed that RA produced significant fibrillin-1 deposition in the papillary dermis (P<0.01) but had little effect on procollagen I or matrix metalloproteinase-1 expression. The 6% total active complex formulation, however, increased the deposition of fibrillin-1 and procollagen I (P<0.01, P<0.05, respectively). CONCLUSIONS: This study indicates that in an in vivo 12-day patch test an over-the-counter cosmetic product can induce changes in photoaged dermal extracellular matrix, which are indicative of repair.     

An association between arterial pulse pressure and variation in the fibrillin-1 gene

Objective—To investigate whether variation in the fibrillin-1 gene was associated with blood pressure in healthy middle aged men, as had been observed in patients with abdominal aortic aneurysm.
Design, setting, and patients—Middle aged men (n = 245), aged 50 to 61 years, were recruited from one of the nine general practices participating in the second Northwick Park heart study. Blood samples were obtained for the preparation of genomic DNA and analysis of plasma variables.
Main outcome measures—Systolic, diastolic, and pulse pressures; fibrillin-1 genotype characterised with a four allele variable tandem nucleotide repeat polymorphism in intron 28.
Results—In healthy middle aged men only three common genotypes were observed: 2-2 (frequency 54.1%), 2-3 (16%), and 2-4 (15%). The mean arterial systolic (and pulse) pressure varied according to fibrillin-1 genotype: 2-4 genotype, 126.3 (47.6) mm Hg; 2-2 genotype, 131.0 (51.3) mm Hg; and 2-3 genotype, 135.5 (54.2) mm Hg. The median pulse pressure was 50 mm Hg. Distribution of men around the median pulse pressure, according to genotype, showed a significant trend for patients of 2-4 genotype to have the lowest pulse pressures, those of 2-2 genotype to have intermediate pressures, and those of 2-3 genotype to have the highest pulse pressures (p = 0.003 for healthy men).
Conclusions—There appears to be a significant association between fibrillin-1 genotype and arterial pulse pressure in men aged 50 to 61 years.

Keywords: blood pressure;  fibrillin;  pulse pressure     

FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations

Fibrillin-1 gene ( FBN1 ) mutations cause Marfan syndrome (MFS), an inherited connective tissue disorder with autosomal dominant transmission. Major clinical manifestations affect cardiovascular and skeletal apparatuses and ocular and central nervous systems. We analyzed FBN1 gene in 99 patients referred to our Center for Marfan Syndrome and Related Disorders (University of Florence, Florence, Italy): 85 were affected by MFS and 14 by other fibrillinopathies type I. We identified mutations in 80 patients. Among the 77 different mutational events, 46 had not been previously reported. They are represented by 49 missense (61%), 1 silent (1%), 13 nonsense (16%), 6 donor splice site mutations (8%), 8 small deletions (10%), and 3 small duplications (4%). The majority of missense mutations were within the calcium-binding epidermal growth factor-like domains. We found preferential associations between The Cys-missense mutations and ectopia lentis and premature termination codon mutations and skeletal manifestations. In contrast to what reported in literature, the cardiovascular system is severely affected also in patients carrying mutations in exons 1–10 and 59–65. In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.     

Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies

Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin-1 FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association. Hum Mutat 10:415–423, 1997. © 1997 Wiley-Liss, Inc.