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The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells.

ABSTRACT: Elastic fibers are critical for the mechanical function of the large arteries. Mechanical effects of elastic fiber protein deficiency have been investigated in whole arteries, but not in isolated smooth muscle cells (SMCs). The elastic moduli of SMCs from elastin (Eln-/-) and fibulin-4 (Fbln4-/-) knockout mice were measured using atomic force microscopy. Compared to control SMCs, the modulus of Eln-/- SMCs is reduced by 40%, but is unchanged in Fbln4-/- SMCs. The Eln-/- SMC modulus is rescued by soluble or ? elastin treatment. Altered gene expression, specifically of calponin, suggests that SMC phenotypic modulation may be responsible for the modulus changes.

SUBMITTER: Gabriela Espinosa M

PROVIDER: S-EPMC5101025 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells.

Gabriela Espinosa M M Gardner William S WS Bennett Lisa L Sather Bradley A BA Yanagisawa Hiromi H Wagenseil Jessica E JE

Journal of biomechanical engineering 20140201 2

Elastic fibers are critical for the mechanical function of the large arteries. Mechanical effects of elastic fiber protein deficiency have been investigated in whole arteries, but not in isolated smooth muscle cells (SMCs). The elastic moduli of SMCs from elastin (Eln-/-) and fibulin-4 (Fbln4-/-) knockout mice were measured using atomic force microscopy. Compared to control SMCs, the modulus of Eln-/- SMCs is reduced by 40%, but is unchanged in Fbln4-/- SMCs. The Eln-/- SMC modulus is rescued by ...[more]

PMID: 24322348

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Project description:The chronic overexpression of matrix metalloproteases leading to consequent degradation and loss of the elastic matrix with the reduction in tissue elasticity is central to the pathophysiology of proteolytic disorders, such as abdominal aortic aneurysms (AAAs), which are localized rupture-prone aortic expansions. Effecting tissue repair to alleviate this condition is contingent on restoring elastic matrix homeostasis in the aortic wall. This is naturally irreversible due to the poor elastogenicity of adult and diseased vascular cells, and the impaired ability to assemble mature elastic fibers, more so in the context of phenotypic changes to medial smooth muscle cells (SMCs) owing to the loss of nitric oxide (NO) signaling in the AAA wall tissue. In this study, we report the benefits of the exposure of primary human aneurysmal SMCs (aHASMCs) to NO donor drug, sodium nitroprusside (SNP), in improving extracellular matrix homeostasis, particularly aspects of elastic fiber assembly, and inhibition of proteolytic degradation. SNP treatment (100 nM) upregulated elastic matrix regeneration at both gene (p < 0.05) and protein levels (p < 0.01) without affecting cell proliferation, improved gene, and protein expression of crosslinking enzyme, lysyl oxidase (p < 0.05), inhibited the expression of MMP2 (matrix metalloprotease 2) significantly (p < 0.05) and promoted contractile SMC phenotypes in aHASMC culture. In addition, SNP also attenuated the expression of mitogen-activated protein kinases, a significant player in AAA formation and progression. Our results indicate the promise of SNP for therapeutic augmentation of elastic matrix regeneration, with prospects for wall repair in AAAs. Impact Statement Chronic and naturally irreversible enzymatic degradation and loss of elastic fibers are centric to proteolytic disorders such as abdominal aortic aneurysms (AAAs). This is linked to poor elastogenicity of adult and diseased vascular cells, compromising their ability to assemble mature elastic fibers. Toward addressing this, we demonstrate the phenotype-modulatory properties of a nitric oxide donor drug, sodium nitroprusside on aneurysmal smooth muscle cells, and its dose-specific proelastogenic and antiproteolytic properties for restoring elastic matrix homeostasis. Combined with the development of vehicles for site-localized, controlled drug delivery, this can potentially lead to a new nonsurgical approach for AAA wall repair in the future.

Dataset Information

The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells.

Publications

The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells.

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