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Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging.

ABSTRACT: RATIONALE:Increased aortic stiffness, an important feature of many vascular diseases, eg, aging, hypertension, atherosclerosis, and aortic aneurysms, is assumed because of changes in extracellular matrix (ECM). OBJECTIVE:We tested the hypothesis that the mechanisms also involve intrinsic stiffening of vascular smooth muscle cells (VSMCs). METHODS AND RESULTS:Stiffness was measured in vitro both by atomic force microscopy (AFM) and in a reconstituted tissue model, using VSMCs from aorta of young versus old male monkeys (Macaca fascicularis) (n=7/group), where aortic stiffness increases by 200% in vivo. The apparent elastic modulus was increased (P<0.05) in old (41.7+/-0.5 kPa) versus young (12.8+/-0.3 kPa) VSMCs but not after disassembly of the actin cytoskeleton with cytochalasin D. Stiffness of the VSMCs in the reconstituted tissue model was also higher (P<0.05) in old (23.3+/-3.0 kPa) than in young (13.7+/-2.4 kPa). CONCLUSIONS:These data support the novel concept, not appreciated previously, that increased vascular stiffness with aging is attributable not only to changes in ECM but also to intrinsic changes in VSMCs.

SUBMITTER: Qiu H

PROVIDER: S-EPMC2936100 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging.

Qiu Hongyu H Zhu Yi Y Sun Zhe Z Trzeciakowski Jerome P JP Gansner Meredith M Depre Christophe C Resuello Ranillo R G RR Natividad Filipinas F FF Hunter William C WC Genin Guy M GM Elson Elliot L EL Vatner Dorothy E DE Meininger Gerald A GA Vatner Stephen F SF

Circulation research 20100715 5

<h4>Rationale</h4>Increased aortic stiffness, an important feature of many vascular diseases, eg, aging, hypertension, atherosclerosis, and aortic aneurysms, is assumed because of changes in extracellular matrix (ECM).<h4>Objective</h4>We tested the hypothesis that the mechanisms also involve intrinsic stiffening of vascular smooth muscle cells (VSMCs).<h4>Methods and results</h4>Stiffness was measured in vitro both by atomic force microscopy (AFM) and in a reconstituted tissue model, using VSMC ...[more]

PMID: 20634486

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Project description:BackgroundAngiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown.Methodology/principal findingsThe present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001.Conclusions/significanceCalpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis.

Dataset Information

Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging.

Publications

Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging.

Similar Datasets

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