Elastin haploinsufficiency induces alternative aging processes in the aorta

Elastin, the main component of elastic fibers, is synthesized only in early life and provides the blood vessels with their elastic properties. With aging, elastin is progressively degraded, leading to arterial enlargement, stiffening, and dysfunction. Also, elastin is a key regulator of vascular smooth muscle cell proliferation and migration during development since heterozygous mutations in its gene (Eln) are responsible for a severe obstructive vascular disease, supravalvular aortic stenosis, isolated or associated to Williams syndrome. Here, we have studied whether early elastin synthesis could also influence the aging processes, by comparing the structure and function of ascending aorta from 6- and 24-month-old Eln+/- and Eln+/+ mice. Eln+/- animals have high blood pressure and arteries with smaller diameters and more rigid walls containing additional although thinner elastic lamellas. Nevertheless, longevity of these animals is unaffected. In young adult Eln+/- mice, some features resemble vascular aging of wild-type animals: cardiac hypertrophy, loss of elasticity of the arterial wall through enhanced fragmentation of the elastic fibers, and extracellular matrix accumulation in the aortic wall, in particular in the intima. In Eln+/- animals, we also observed an age-dependent alteration of endothelial vasorelaxant function. On the contrary, Eln+/- mice were protected from several classical consequences of aging visible in aged Eln+/+ mice, such as arterial wall thickening and alteration of alpha(1)-adrenoceptor-mediated vasoconstriction. Our results suggest that early elastin expression and organization modify arterial aging through their impact on both vascular cell physiology and structure and mechanics of blood vessels

Anomalous structure of urinary glycosaminoglycans in patients with pseudoxanthoma elasticum

Anomalous structure of urinary glycosaminoglycans in patients with pseudoxanthoma elasticu

Ageing of connective tissues

Aging, considered as a chronological and/or biological event, is an extremely complex and multifactorial process, which may represent the consequences of environmental noxae interfering with genetic and developmental programs.The extracellular matrix plays a crucial role in age-related degenerations, and the so-called "premature aging syndromes" give further evidence for the complexity of the relationships between connective tissue, age and diseases. Several reports already focused on the correlations between age and phenotypic expression of mesenchimal cells in vitro; moreover, it was also pointed out that morphological and functional alterations of connective tissues, at some extent, might be related in vivo to increasing age. Correlation between morphologic data and proteomic analyses sustains the hypothesis that senescence is the result of both genetic and epigenetic factors

Identification of mineralized elastic fibers on wet samples by SEM

A method is described that could be of potential use for the rapid ultrastructural identification of abnormal and fragmented elastic fibers in very small wet samples of dermal biopsies from patients affected by Pseudoxanthoma elasticum (PXE). Moreover, the method, which consists of the use of sealed capsules transparent to electrons, allows the rapid and accurate localization and detection of mineralized areas in PXE patients and of their ion composition by X-ray microanalysis. This methodology could be of great help in any tissue disorder, especially in connective tissue disorders, characterized by structural alterations associated with ion precipitation

ABCC6 gene analysis in Italian subjects affected by Pseudoxanthoma elasticum.

Techniques used to screen PXE patients for causative mutations in the ABCC6 gene are described and compared in order to reach a better mutation detection rate

Functional genomics: the PXE model

Pseudoxanthoma elasticum represent a disease model for investigating the relationships bettween altered fibroblast phenotype and elastic fiber degeneration/calcification

High levels of desmosines in urine and plasma pf patients with pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE), a rare heritable disorder caused by mutations of the ABCC6 gene, is characterized by fragmentation and mineralization of elastic fibres. We determined the extent of degradation of elastin by measuring and comparing the amount of desmosines in plasma and urine of PXE patients, healthy carriers and normal subjects. METHODS: Using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) we measured the amount of desmosines in the urine of 46 individuals (14 PXE patients, 17 healthy carriers and 15 controls) and in the plasma of 56 subjects (18 PXE patients, 23 healthy carriers and 15 controls). Pseudoxanthoma elasticum patients and carriers were identified by clinical, structural and molecular biology analyses. RESULTS: The urinary excretion of desmosines was two-fold higher in PXE patients than in controls (P < 0.01); the values for healthy carriers were intermediate between those of PXE patients and controls. A very similar trend between patients and their relatives was observed for plasma desmosines. There was a significant correlation between the amount of the desmosines in plasma and urine. Moreover, a positive correlation was observed between urinary desmosine content and age of the patients as well as between urinary desmosine content and severity of clinical manifestations. CONCLUSIONS: Both the urinary and plasma desmosine concentrations indicate that elastin degradation is higher in PXE patients and, to a lesser extent, in healthy carriers than in normal subjects. Data seem to indicate that the amount of elastin breakdown products correlates with the age of patients as well as with the severity of the disease

Is matrix GLA Protein (MGP) a key regulator of elastic fiber calcification?

The role of vitamin k dependent carboxylation of Matrix Gla protein in PXE patogenesis is described and discussed