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

Carotid stenosis - Factors affecting symptomatology

Background and Purpose-The ability to predict future strokes in asymptomatic patients with carotid stenosis is currently limited. The management of symptomatic patients with < 50% stenosis is also debatable, In this context, we performed the following open prospective study to identify factors affecting symptomatology in patients with carotid stenosis. Methods-During 1988-1997, 442 arteries with various degrees of stenosis were followed with the use of color Duplex ultrasonography every 6 months. The main outcome measures were development of symptoms related to the carotid territory and progression in the degree of stenosis. Results Of follow-up were analyzed in relation to the traditional risk factors for atherosclerosis as well as the ultrasonographic characteristics of the plaques. Statistical analysis was performed by multiple linear and Cox regression analysis. Results-Mean duration of follow-up was 44 months (range, 12 to 120 months). Significant progression of stenosis occurred in 18.5% of the cases and was more frequent in younger patients (P = 0.09), in patients with coronary artery disease (P = 0.02), and in patients with echolucent plaques (P = 0.02), In regard to clinical presentation, men (P = 0.07), hypertensives (P = 0.07), and patients with echolucent plaques (P = 0.09) showed a trend toward higher frequency of stroke in their history. During the follow-up period. neurological events developed in 12.4% of the cases and were associated with the severity of carotid disease (P < 0.001), history of neurological events (P = 0.02), progression of stenosis (P = 0.002). echolucent plaques (P = 0.01). and hypertension (P = 0.02). Conclusions-Factors other than de-ree of stenosis and history of neurological events are also important in determining high-risk carotid plaque. In our study hypertension. echolucent plaques, and progressive lesions were associated with an increased risk of neurological events. These factors should be taken into consideration in determining treatment strategies for carotid stenosis

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

Risk factors associated with recurrent carotid artery stenosis

The aim of this open, perspective study was to determine the impact of risk factors, excluding the type of closure of the arteriotomy, in the development of recurrent carotid stenosis following carotid endarterectomy. One hundred and ninety-eight patients, who underwent a total of 221 carotid endarterectomies, were evaluated postoperatively with duplex scanning 1 month after the operation and every 6 months thereafter for a period of 6-120 months (mean duration of follow-up: 44 months). There were 149 (75.3%) men and 49 (24.7%) women with a mean age of 66.8 years (age range 38-92 years). Diabetes mellitus was present in 62 patients (31.3%), hypertension in 134 (67.7%), coronary artery disease in 130 (65.7%), hypercholesterolemia in 70 (35.4%), and smoking habit in 166 (83.8%). Indications for carotid endarterectomy were asymptomatic carotid stenosis > 70% in 20 (10.1%) patients and symptomatic stenosis > 50% in 178 (89.9%), 129 (65.2%) of whom had a history of transient ischemic attacks and 49 (24.7%) of previous stroke. General anesthesia was used in 197 (89.1%) operations and local anesthesia in 24 (10.9%). Deep endarterectomy with primary closure of the arteriotomy using 5/0 running suture was performed in this group of patients. One patient: (0.5%) died during the perioperative period. Five (2.5%) patients had a transient ischemic attack and three (1.5%) a nonfatal stroke in the immediate postoperative period, six (3.0%) a persistent cranial nerve injury, and two a hematoma, and three patients had delayed postoperative recovery. Twenty-six (13.1%) patients were transferred to the Intensive Care Unit postoperatively, Recurrent carotid stenosis > 50% was identified in eight patients (4.0%) and it was asymptomatic in all cases; Mean interval between endarterectomy and development of restenosis was 47.4 months (range 6-118 months). Factors such as clinical presentation, age, sex, diabetes mellitus, hypertension, coronary artery disease, hypercholesterolemia, and smoking habit were not found to be significantly associated with the development: of restenosis (Chi-square). Smoking, coronary artery disease, and normal choresterol levels were connected with a statistically nonsignificant tendency toward higher rates of restenosis. Recurrent carotid stenosis following carotid endarterectomy was not significantly associated with any of the risk factors studied in this series