A Dynamic Stochastic Model of Frequency-Dependent Stress Fiber Alignment Induced by Cyclic Stretch

BACKGROUND: Actin stress fibers (SFs) are mechanosensitive structural elements that respond to forces to affect cell morphology, migration, signal transduction and cell function. Cells are internally stressed so that SFs are extended beyond their unloaded lengths, and SFs tend to self-adjust to an equilibrium level of extension. While there is much evidence that cells reorganize their SFs in response to matrix deformations, it is unclear how cells and their SFs determine their specific response to particular spatiotemporal changes in the matrix. METHODOLOGY/PRINCIPAL FINDINGS: Bovine aortic endothelial cells were subjected to cyclic uniaxial stretch over a range of frequencies to quantify the rate and extent of stress fiber alignment. At a frequency of 1 Hz, SFs predominantly oriented perpendicular to stretch, while at 0.1 Hz the extent of SF alignment was markedly reduced and at 0.01 Hz there was no alignment at all. The results were interpreted using a simple kinematic model of SF networks in which the dynamic response depended on the rates of matrix stretching, SF turnover, and SF self-adjustment of extension. For these cells, the model predicted a threshold frequency of 0.01 Hz below which SFs no longer respond to matrix stretch, and a saturation frequency of 1 Hz above which no additional SF alignment would occur. The model also accurately described the dependence of SF alignment on matrix stretch magnitude. CONCLUSIONS: The dynamic stochastic model was capable of describing SF reorganization in response to diverse temporal and spatial patterns of stretch. The model predicted that at high frequencies, SFs preferentially disassembled in the direction of stretch and achieved a new equilibrium by accumulating in the direction of lowest stretch. At low stretch frequencies, SFs self-adjusted to dissipate the effects of matrix stretch. Thus, SF turnover and self-adjustment are each important mechanisms that cells use to maintain mechanical homeostasis

Artificial blood vessel: The Holy Grail of peripheral vascular surgery

Artificial blood vessels composed of viable tissue represent the ideal vascular graft. Compliance, lack of thrombogenicity, and resistance to infections as well as the ability to heal, remodel, contract, and secrete normal blood vessel products are theoretical advantages of such grafts. Three basic elements are generally required for the construction of an artificial vessel: a structural scaffold, made either of collagen or a biodegradable polymer; vascular cells, and a nurturing environment. Mechanical properties of the artificial vessels are enhanced by bioreactors that mimic the in vivo environment of the vascular cells by producing pulsatile flow. Alternative approaches include the production of fibrocollagenous tubes within the recipient’s own body (subcutaneous tissue or peritoneal cavity) and the construction of an artificial vessel from acellular native tissues, such as decellularized small intestine submucosa, ureter, and allogeneic or xenogeneic arteries. This review details the most recent developments on vascular tissue engineering, summarizes the results of initial experiments on animals and humans, and outlines the current status and the challenges for the future

Inflammation and atherosclerosis

Purpose. The aim of this article is to discuss the role of inflammation in atherosclerosis. Summary. An initial chemical, mechanical or immunological insult induces endothelial dysfunction. This triggers a cascade of inflammatory reactions, in Which monocytes, macrophages, T lymphocytes and vascular smooth muscle cells participate. Leukocyte adhesion molecules, cytokines, growth factors and metalloproteinases participate in all stages of atherogenesis. Almost all of the traditional risk factors for atherosclerosis are associated with and participate in the inflammatory process. Many infectious agents, mainly Chlamydia pneumoniae, have been proposed as potential triggers of the cascade. The immune system has been implicated in plaque formation, through the activation of cellular and humoral immunity against innate or microbial heat shock protein 60. Methods of detection of systemic or local plaque inflammation have been developed and research is being conducted on the potential use of anti-inflammatory and antibiotic drugs in atherosclerosis

The role of STAT-3 in the mediation of smooth muscle cell response to cyclic strain

Hemodynamic forces, including shear stress and cyclic strain, have been recognised as important modulators of vascular cell morphology and function. However, the mechanism by which vascular cells sense and transduce the extracellular mechanical signals into the cell nucleus has not yet been clarified. The purpose of our study was to assess the involvement of the signal transducer and activator of transcription-3 (STAT-3) in the signaling pathway mediating the response of vascular smooth muscle cells (SMC) to cyclic strain. Embryonic A7r5 SMC derived from thoracic aortas of DB 1X rats were seeded on flexible collagen I-coated plates. Cells were subjected to 10% average strain at 60 cycles/min for various time periods. Activation of STAT-3, p38, extracellular signal -regulated kinase (ERK) 1/2 and Src was assessed by immunoblotting using phosphospecific antibodies. The interactions between STAT-3 phosphorylation and p38, ERK 1 /2, phosphatidylinositol-3 (PI3K), mammalian target of rapamycin (mTOR), Janus kinase (JAK) 2 and Src were evaluated by pretreating the cells with specific inhibitors including SB202190, PD98059, LY294002, wortmannin, rapamycin, AG490 and PP I. Serine phosphorylation of STAT-3 was increased by 2-fold after 15 min of cyclic strain, while tyrosine phosphorylation was increased by 2.3-fold after 60 min. Inhibition of ERK 1/2 by PD98059 prevented serine phosphorylation of STAT-3, whereas inhibition of Src by PP1 prevented STAT-3 tyrosine phosphorylation. Pretreating the cells with SB202190, a specific inhibitor of p38, resulted in an increase in basal phosphorylation of ERK1/2 and a subsequent increase in basal serine phosphorylation of STAT-3. In conclusion, both serine and tyrosine phosphorylation of STAT-3 are involved in the signaling pathway mediating the effects of cyclic strain on vascular SMC. Serine phosphorylation of STAT-3 is mediated by ERK1/2, while tyrosine phosphorylation is mediated by Re. A negative feedback loop was also found between p38 and ERK 1 /2. (c) 2005 Elsevier Ltd. All rights reserved