Many extensible tissues such as skin, lungs, and blood vessels require elasticity to function properly. The recoil of elastic energy stored during a stretching phase is provided by elastic fibers, which are mostly composed of elastin and fibrillin-rich microfibrils. In arteries, the lack of elastic fibers leads to a weakening of the vessel wall with an increased risk to develop cardiovascular defects such as stenosis, aneurysms, and dissections. The development of new therapeutic molecules involves preliminary tests in animal models that recapitulate the disease and whose response to drugs should be as close as possible to that of humans. Due to its superior in vivo imaging possibilities and the broad tool kit for forward and reverse genetics, the zebrafish has become an important model organism to study human pathologies. Moreover, it is particularly adapted to large scale studies, making it an attractive model in particular for the first steps of investigations. In this review, we discuss the relevance of the zebrafish model for the study of elastic fiber-related vascular pathologies. We evidence zebrafish as a compelling alternative to conventional mouse models.

Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only.
In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations.
A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants.
This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.

We investigated the antiwrinkle effects of cultured human fibroblasts and adipose-derived stem cells (ADSCs) and the mechanisms underlying the reduction of wrinkles in photoaged skin. The fibroblasts and ADSCs were isolated from human tissue and cultured. A total of 28 6-week-old female BALB/c nude mice were classified into four groups, including the normal control group and three groups that were irradiated six times a week for 6-weeks using ultraviolet B radiation to induce photoaged wrinkles. ADSCs were injected into the wrinkles in the skin of the second group and fibroblasts were injected into the wrinkles in the skin of the third group. The fourth group was the irradiated negative control group (no therapy). After 4 weeks of injections, the wrinkles were compared by replica analysis, biopsies were performed, and the dermal thickness and collagen densities were measured. We determined the amounts of type 1 collagen and matrix metalloproteinases (MMPs) 1, 2, 3, 9, and 13 using real-time polymerase chain reaction and Western blot analysis, and we assessed tropoelastin and fibrillin-1 expression in the dermis by immunohistochemistry. Replica analysis showed significant wrinkle reduction in the fibroblast group and the ADSC group. ADSCs stimulated collagen expression and decreased MMP expression. Although fibroblasts stimulated more collagen expression than ADSCs, they also increased MMP expression. Overall, the ADSC group showed higher collagen density and had better outcomes in the tropoelastin and fibrillin-1 assessments. Both cultured fibroblasts and ADSCs could play an important role in wrinkle reduction despite differences in their mechanisms of action.

Photoaging accounts for most age-related changes in skin appearance. It has been suggested that both astaxanthin, a potent antioxidant, and collagen hydrolysate can be used as antiaging modalities in photoaged skin. However, there is no clinical study using astaxanthin combined with collagen hydrolysate. We investigated the effects of using a combination of dietary astaxanthin and collagen hydrolysate supplementation on moderately photoaged skin in humans. A total of 44 healthy subjects were recruited and treated with astaxanthin (2 mg/day) combined with collagen hydrolysate (3 g/day) or placebos, which were identical in appearance and taste to the active supplementation for 12 weeks. The elasticity and hydration properties of facial skin were evaluated using noninvasive objective devices. In addition, we also evaluated the expression of procollagen type I, fibrillin-1, matrix metalloproteinase-1 (MMP-1) and -12, and ultraviolet (UV)-induced DNA damage in artificially UV-irradiated buttock skin before and after treatment. The supplement group showed significant improvements in skin elasticity and transepidermal water loss in photoaged facial skin after 12 weeks compared with the placebo group. In the supplement group, expression of procollagen type I mRNA increased and expression of MMP-1 and -12 mRNA decreased compared with those in the placebo group. In contrast, there was no significant difference in UV-induced DNA damage between groups. These results demonstrate that dietary astaxanthin combined with collagen hydrolysate can improve elasticity and barrier integrity in photoaged human facial skin, and such treatment is well tolerated.

Fibrillin-1 (FBN1) was reported to have impact on the physiological arterial stiffness and vascular remodeling with hypertension of recent years. In the previous study we reported the association of four functional single nucleotide polymorphisms (SNPs) of FBN1 gene and hypertension. Here, we further investigate the association of four tagging SNPs (tagSNPs) which covered remain genetic variation blocks of FBN1 gene with hypertension, blood pressure and efficacy of antihypertensive in a South Han Chinese population. A case-control study including 2,012 hypertension cases and 2,116 controls age- and sex-matched controls was conducted from a community-based population and four candidate tagSNPs of the FBN1 gene were genotyped. Association analysis by multiple logistic regression was conducted for allele, genotype and haplotype and hypertension, blood pressure trait and control status with antihypertensive. General linear model was applied to compare blood pressure levels between genotypes. The association of rs17361868 and hypertension was statistically significant and that was further observed in female, ≥55 years, non-smoking and non-drinking populations (P < 0.05). Significant association of rs668842, rs11635140 and hypertension were observed in <55 years population as well as the later in female and non-smoking populations respectively. Haplotype G-T constructed of rs668842 and rs11635140 was significantly associated with hypertension comparing to reference haplotype A-C (P = 0.022). Normally distributed square root of TGF-β1 (pg/ml) of hypertension cases (148.56 ± 66.46) was significantly higher than that of control (128.52 ± 65.11), P = 0.008. Furthermore, TGF-β1 was significantly correlated with SBP (r = 0.135, P = 0.018) and DBP (r = 0.154, P = 0.007) respectively whereas no statistical difference of blood pressure or TGF-β1 was observed between genotypes. Remarkably, rs17361868 were significantly associated with the status of blood pressure in the patients taking three of the antihypertensive drugs, Zhen Ju Jiang Ya tablets, Jiang Ya tablet and compound reserpine (P < 0.05). The present study provides further association evidence of FBN1 gene polymorphisms and hypertension, antihypertensive efficacy. Further replication of these results via association or prospective studies conducted in other populations is warranted.

BACKGROUND: Marfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation.
RESULTS: We performed an observational cohort study of 80 consecutive adults (30 men, 50 women aged 42±15 years) with Marfan syndrome caused by FBN1 mutations. We assessed ventricular arrhythmia on baseline ambulatory electrocardiography as >10 premature ventricular complexes per hour (>10 PVC/h), as ventricular couplets (Couplet), or as non-sustained ventricular tachycardia (nsVT), and during 31±18 months of follow-up as ventricular tachycardia (VT) events (VTE) such as sudden cardiac death (SCD), and sustained ventricular tachycardia (sVT). We identified >10 PVC/h in 28 (35%), Couplet/nsVT in 32 (40%), and VTE in 6 patients (8%), including 3 with SCD (4%). PVC>10/h, Couplet/nsVT, and VTE exhibited increased N-terminal pro-brain natriuretic peptide serum levels(P<.001). All arrhythmias related to increased NT-proBNP (P<.001), where PVC>10/h and Couplet/nsVT also related to increased indexed end-systolic LV diameters (P = .024 and P = .020), to moderate mitral valve regurgitation (P = .018 and P = .003), and to prolonged QTc intervals (P = .001 and P = .006), respectively. Moreover, VTE related to mutations in exons 24-32 (P = .021). Kaplan-Meier analysis corroborated an association of VTE with increased NT-proBNP (P<.001) and with mutations in exons 24-32 (P<.001).
CONCLUSIONS: Marfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring. Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24-32 may be risk factors of VTE.

OBJECTIVE: Because diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age.
METHODS: Two hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children.
RESULTS: Prevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0-6 years to 62% at 15-17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving β-blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating.
CONCLUSIONS: Ectopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a β-blocker.

A single instillation of porcine pancreatic elastase (PPE) results in significant airspace enlargement on the 28th day after instillation, whereas cigarette smoke (CS) exposure requires 6 months to produce mild emphysema in rodents. Considering that there are differences in the pathogenesis of parenchymal destruction in these different experimental models, it is likely that there may be different patterns of extracellular matrix (ECM) remodeling. To evaluate ECM remodeling, C57BL/6 mice were submitted to either a nasal drop of PPE (PPE 28 Days) or exposed for 6 months to cigarette smoke (CS 6 months). Control groups received either an intranasal instillation of saline solution (Saline 28 Days) or remained without any smoke inhalation for six months (Control 6 months). We measured the mean linear intercept and the volume proportion of collagen type I, collagen type III, elastin and fibrillin. We used emission-scanning confocal microscopy to verify the fiber distribution. Both models induced increased mean linear intercept in relation to the respective controls, being larger in the elastase model in relation to the CS model. In the CS model, emphysema was associated with an increase in the volume proportion of fibrillin, whereas in the PPE model there was an increase in the parenchymal elastin content. In both models, there was an increase in collagen type III, which was higher in the CS-exposed mice. We concluded that ECM remodeling is different in the two most used experimental models of emphysema.

The D19S884 marker at the fibrillin 3 gene has been analysed as a candidate location for polycystic ovary syndrome (PCOS) mainly in Caucasian descendants. A case-control study was performed with 272 PCOS women and 271 controls to test the hypothesis that variants in the D19S884 marker increase susceptibility to PCOS in Chinese women and a meta-analysis was undertaken to clarify whether there is an allele consistently contributing to the susceptibility. The association analysis showed that PCOS women were significantly different from controls in the distribution of D19S884 allele frequencies. Instead of the well-known A8 allele, the most common allele in Chinese population was proved to be A7, and the allele frequencies of A7 were statistically different between cases and controls (P=0.037). The meta-analysis of A8 and A7 only identified A8 as a significant allelic association at the D19S884 marker in all combined samples (A8: OR 1.391, 95% CI 1.169-1.654; A7: OR 1.154, 95% CI 0.894-1.490). In conclusion, the association study showed a potential association of the D19S884 marker with PCOS in Chinese Han women and the meta-analysis identified that A8 may increase susceptibility to PCOS. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and it affects an estimated 15% of women worldwide based on the Rotterdam criteria. Many studies in Caucasian descendants suggested that variants of the D19S884 marker at the fibrillin 3 gene are associated with the risk of this syndrome. Here we performed a case-control study with 272 PCOS women and 271 controls to investigate whether variants in the D19S884 marker increase susceptibility to PCOS in Chinese women. We also carried out a meta-analysis of some relevant studies to find a more reliable result. Our association analysis showed that PCOS women were significantly different from controls in the distribution of D19S884 allele frequencies, and instead of the well-known A8 (the letter \'A\' represents \'allele\'), the most common allele in Chinese population was proved to be A7, whose allele frequencies were statistically different between cases and controls. The meta-analysis of A8 and A7 only identified A8 as a significant allelic association at the D19S884 marker in all combined samples. In conclusion, our association study showed a potential association of the D19S884 marker with PCOS in Chinese Han women and the meta-analysis identified that A8 may increase susceptibility to PCOS.

We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.