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The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification.

Lefthériotis G, Omarjee L, Le Saux O, Henrion D, Abraham P, Prunier F, Willoteaux S, Martin L - Front Genet (2013)

Bottom Line: The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin.The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date.Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

View Article: PubMed Central - PubMed

Affiliation: PXE Health and Research Centre, University Hospital of Angers Angers, France ; L'UNAM, UMR CNRS 6214 - Inserm 1083, Medical School of Angers Angers, France.

ABSTRACT
Vascular calcification is a complex and dynamic process occurring in various physiological conditions such as aging and exercise or in acquired metabolic disorders like diabetes or chronic renal insufficiency. Arterial calcifications are also observed in several genetic diseases revealing the important role of unbalanced or defective anti- or pro-calcifying factors. Pseudoxanthoma elasticum (PXE) is an inherited disease (OMIM 264800) characterized by elastic fiber fragmentation and calcification in various soft conjunctive tissues including the skin, eyes, and arterial media. The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin. The clinical expression of the PXE arterial disease is characterized by an increased risk for coronary (myocardial infarction), cerebral (aneurysm and stroke), and lower limb peripheral artery disease. However, the structural and functional changes in the arterial wall induced by PXE are still unexplained. The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date. Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

No MeSH data available.


Related in: MedlinePlus

Anterior and posterior 3D-views of lower limb arterial calcification in pseudoxanthoma elasticum revealed with helicoidal X-ray tomodensitometry. Calcification in the femoral artery is tagged in green, the popliteal in purple, and the visible distal arteries are tagged in blue. Note the absence of calcifications within the middle popliteal segment.
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Figure 1: Anterior and posterior 3D-views of lower limb arterial calcification in pseudoxanthoma elasticum revealed with helicoidal X-ray tomodensitometry. Calcification in the femoral artery is tagged in green, the popliteal in purple, and the visible distal arteries are tagged in blue. Note the absence of calcifications within the middle popliteal segment.

Mentions: The macroscopic distribution of the calcification along the arterial tree can be mapped using standard X-ray, although 3D reconstruction using helicoidal X-rays scans provides a more precise quantification and site identification (see Figure 1). In our experience, calcification accumulates mostly within the distal superficial femoral and below-knee arteries (tibialis and pedalis), a distribution mostly observed in the arteriosclerotic process associated with aging. Skin lesions are extensively documented in PXE, as skin biopsy are routinely done for diagnosis. However, histologic findings of the PXE-related vascular lesion are sparse and obtained from rare available autopsy samples. Ultrastructural analysis from the ascending aorta, iliac arteries, and vena cava from 2 males with PXE (36 and 80 years old), revealed that veins and arteries were similarly damaged (Gheduzzi et al., 2003). The alterations were not distributed homogeneously along the vessels with spotty alterations of elastic fibers, and aggregates of thin strands of amorphous elastin. The von Kossa staining revealed calcium sediment within the medial layers of the arterial wall of medium (e.g., carotids)- or small (radial)-sized arteries. In carotids, calcification was found extracellularly around elastin fibers although slight increase in intracellular calcium is also observed. Elastic fibers appears fragmented and proteoglycans accumulated preferentially within the media rather than intima compared to controls (Kornet et al., 2004). Qualitative and quantitative alteration in proteoglycans metabolism have been reported with increased heparin sulfate and decreased chondroitin sulfate in patient’s urine (Maccari et al., 2003).


The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification.

Lefthériotis G, Omarjee L, Le Saux O, Henrion D, Abraham P, Prunier F, Willoteaux S, Martin L - Front Genet (2013)

Anterior and posterior 3D-views of lower limb arterial calcification in pseudoxanthoma elasticum revealed with helicoidal X-ray tomodensitometry. Calcification in the femoral artery is tagged in green, the popliteal in purple, and the visible distal arteries are tagged in blue. Note the absence of calcifications within the middle popliteal segment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569880&req=5

Figure 1: Anterior and posterior 3D-views of lower limb arterial calcification in pseudoxanthoma elasticum revealed with helicoidal X-ray tomodensitometry. Calcification in the femoral artery is tagged in green, the popliteal in purple, and the visible distal arteries are tagged in blue. Note the absence of calcifications within the middle popliteal segment.
Mentions: The macroscopic distribution of the calcification along the arterial tree can be mapped using standard X-ray, although 3D reconstruction using helicoidal X-rays scans provides a more precise quantification and site identification (see Figure 1). In our experience, calcification accumulates mostly within the distal superficial femoral and below-knee arteries (tibialis and pedalis), a distribution mostly observed in the arteriosclerotic process associated with aging. Skin lesions are extensively documented in PXE, as skin biopsy are routinely done for diagnosis. However, histologic findings of the PXE-related vascular lesion are sparse and obtained from rare available autopsy samples. Ultrastructural analysis from the ascending aorta, iliac arteries, and vena cava from 2 males with PXE (36 and 80 years old), revealed that veins and arteries were similarly damaged (Gheduzzi et al., 2003). The alterations were not distributed homogeneously along the vessels with spotty alterations of elastic fibers, and aggregates of thin strands of amorphous elastin. The von Kossa staining revealed calcium sediment within the medial layers of the arterial wall of medium (e.g., carotids)- or small (radial)-sized arteries. In carotids, calcification was found extracellularly around elastin fibers although slight increase in intracellular calcium is also observed. Elastic fibers appears fragmented and proteoglycans accumulated preferentially within the media rather than intima compared to controls (Kornet et al., 2004). Qualitative and quantitative alteration in proteoglycans metabolism have been reported with increased heparin sulfate and decreased chondroitin sulfate in patient’s urine (Maccari et al., 2003).

Bottom Line: The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin.The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date.Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

View Article: PubMed Central - PubMed

Affiliation: PXE Health and Research Centre, University Hospital of Angers Angers, France ; L'UNAM, UMR CNRS 6214 - Inserm 1083, Medical School of Angers Angers, France.

ABSTRACT
Vascular calcification is a complex and dynamic process occurring in various physiological conditions such as aging and exercise or in acquired metabolic disorders like diabetes or chronic renal insufficiency. Arterial calcifications are also observed in several genetic diseases revealing the important role of unbalanced or defective anti- or pro-calcifying factors. Pseudoxanthoma elasticum (PXE) is an inherited disease (OMIM 264800) characterized by elastic fiber fragmentation and calcification in various soft conjunctive tissues including the skin, eyes, and arterial media. The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin. The clinical expression of the PXE arterial disease is characterized by an increased risk for coronary (myocardial infarction), cerebral (aneurysm and stroke), and lower limb peripheral artery disease. However, the structural and functional changes in the arterial wall induced by PXE are still unexplained. The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date. Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

No MeSH data available.


Related in: MedlinePlus