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Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2014 May; Vol. 34 (5), pp. 1045-56. Date of Electronic Publication: 2014 Mar 27. - Publication Year :
- 2014
-
Abstract
- Objective: Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6(-/-) mice, a model of the human disease.<br />Approach and Results: Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6(-/-) than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6(-/-) arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6(-/-) arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6(-/-) arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6(-/-), despite higher variability.<br />Conclusions: Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6(-/-) mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.
- Subjects :
- ATP-Binding Cassette Transporters genetics
Animals
Arterial Pressure
Arteries pathology
Arteries physiopathology
Biomarkers metabolism
Cell Transdifferentiation
Chondrogenesis
Collagen Type II genetics
Collagen Type II metabolism
Core Binding Factor Alpha 1 Subunit genetics
Core Binding Factor Alpha 1 Subunit metabolism
Disease Models, Animal
Elastic Tissue pathology
Elastic Tissue physiopathology
Gene Expression Regulation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Multidrug Resistance-Associated Proteins
Osteogenesis
Osteopontin genetics
Osteopontin metabolism
Pseudoxanthoma Elasticum genetics
Pseudoxanthoma Elasticum pathology
Pseudoxanthoma Elasticum physiopathology
RNA, Messenger metabolism
Regional Blood Flow
SOXB1 Transcription Factors genetics
SOXB1 Transcription Factors metabolism
Vascular Calcification genetics
Vascular Calcification pathology
Vascular Calcification physiopathology
ATP-Binding Cassette Transporters deficiency
Arteries metabolism
Calcium metabolism
Elastic Tissue metabolism
Pseudoxanthoma Elasticum metabolism
Vascular Calcification metabolism
Vascular Stiffness
Vasoconstriction
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 34
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 24675664
- Full Text :
- https://doi.org/10.1161/ATVBAHA.113.302943