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With every beat of the heart, inflation of the lung or peristalsis of the gut, cell types of diverse function are subjected to substantial stretch. Stretch is a potent stimulus for growth, differentiation, migration, remodelling and gene expression 1,2 . Here, we report that in response to transient stretch the cytoskeleton fluidizes in such a way as to define a universal response class. This finding implicates mechanisms mediated not only by specific signalling intermediates, as is usually assumed, but also by non-specific actions of a slowly evolving network of physical forces. These results support the idea that the cell interior is at once a crowded chemical space 3 and a fragile soft material in which the effects of biochemistry, molecular crowding and physical forces are complex and inseparable, yet conspire nonetheless to yield remarkably simple phenomenological laws. These laws seem to be both universal and primitive, and thus comprise a striking intersection between the worlds of cell biology and soft matter physics.Soft materials such as tomato ketchup, shaving foam and tooth-paste tend to fluidize when subjected to shear 4-7 , as do granular materials including sugar in a bowl, coffee beans in a chute 8 and even certain geophysical strata during an earthquake 9 ; each transforms from a solidlike to a fluid-like phase, stiffness falls, and the material flows. Underlying microscopic stressbearing elements, or clusters of elements, interact with neighbours to form a network of force transmission, but how flow is initiated and the nature of energy barriers that must be overcome remain the subject of much current attention 5-9 .The response of a living cell to transient stretch would seem to be a different matter altogether. Very early literature shows that in response to application of a physical force the cell acutely softens (Supplementary Note 4), but more recent literature uniformly emphasizes stiffening Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to J.J.F. (jeffrey_fredberg@harvard.edu). Author Contributions X.T. and J.J.F. designed research and wrote the manuscript. J.P.B. conducted the theoretical analysis. X.T. and D.N. designed and implemented the experimental system. X.T., L.D. and S.S.A. optimized experimental conditions and treatments. W.T.G. and D.J.T. helped to design experimental protocols and interpret data. D.J.T. provided cells and reagents. X.T. performed all stretch experiments and data analysis. J.J.F. oversaw the project. Shear fluidization of inert matter is usually attributed to the presence of physical interactions that possess energy barriers that are so large that thermal energies by themselves are insufficient to drive microconfigurations to thermodynamic equilibrium. The material is then unable to explore its configuration space 5 , and structural rearrangements become limited by long-lived microconfigu...

Abstract-Smooth muscle cell migration occurs during vascular development, in response to vascular injury, and during atherogenesis. Many proximal signals and signal transduction pathways activated during migration have been identified, as well as components of the cellular machinery that affect cell movement. In this review, a summary of promigratory and antimigratory molecules belonging to diverse chemical and functional families is presented, along with a summary of key signaling events mediating migration. Extracellular molecules that modulate migration include small biogenic amines, peptide growth factors, cytokines, extracellular matrix components, and drugs used in cardiovascular medicine. Promigratory stimuli activate signal transduction cascades that trigger remodeling of the cytoskeleton, change the adhesiveness of the cell to the matrix, and activate motor proteins. This review focuses on the signaling pathways and effector proteins regulated by promigratory and antimigratory molecules. Prominent pathways include phosphatidylinositol 3-kinases, calcium-dependent protein kinases, Rho-activated protein kinase, p21-activated protein kinases, LIM kinase, and mitogen-activated protein kinases. Important downstream targets include myosin II motors, actin capping and severing proteins, formins, profilin, cofilin, and the actin-related protein-2/3 complex. Actin filament remodeling, focal contact remodeling, and molecular motors are coordinated to cause cells to migrate along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. The result is recruitment of cells to areas where the vessel wall is being remodeled. Vessel wall remodeling can be antagonized by common cardiovascular drugs that act in part by inhibiting vascular smooth muscle cell migration. Several therapeutically important drugs act by inhibiting cell cycle progression, which may reduce the population of migrating cells. (Circ Res. 2007;100:607-621.)

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Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Smooth muscle cells are able to adapt rapidly to chemical and mechanical signals impinging on the cell surface. It has been suggested that dynamic changes in the actin cytoskeleton contribute to the processes of contractile activation and mechanical adaptation in smooth muscle. In this review, evidence for functionally important changes in actin polymerization during smooth muscle contraction is summarized. The functions and regulation of proteins associated with "focal adhesion complexes" (membrane-associated dense plaques) in differentiated smooth muscle, including integrins, focal adhesion kinase (FAK), c-Src, paxillin, and the 27-kDa small heat shock protein (HSP27) are described. Integrins in smooth muscles are key elements of mechanotransduction pathways that communicate with and are regulated by focal adhesion proteins that include FAK, c-Src, and paxillin as well as proteins known to mediate cytoskeletal remodeling. Evidence that functions of FAK and c-Src protein kinases are closely intertwined is discussed as well as evidence that focal adhesion proteins mediate key signal transduction events that regulate actin remodeling and contraction. HSP27 is reviewed as a potentially significant effector protein that may regulate actin dynamics and cross-bridge function in response to activation of p21-activated kinase and the p38 mitogen-activated protein kinase signaling pathway by signaling pathways linked to integrin proteins. These signaling pathways are only part of a large number of yet to be defined pathways that mediate acute adaptive responses of the cytoskeleton in smooth muscle to environmental stimuli.

Chronic airways diseases, including asthma, are associated with an increased airway smooth muscle (ASM) mass, which may contribute to chronic airway hyperresponsiveness. Increased muscle mass is due, in part, to increased ASM proliferation, although the precise molecular mechanisms for this response are not completely clear. Caveolae, which are abundant in smooth muscle cells, are membrane microdomains where receptors and signaling effectors can be sequestered. We hypothesized that caveolae and caveolin-1 play an important regulatory role in ASM proliferation. Therefore, we investigated their role in p42/p44 MAPK signaling and proliferation using human ASM cell lines. Disruption of caveolae using methyl-beta-cyclodextrin and small interfering (si)RNA-knockdown of caveolin-1 caused spontaneous p42/p44 MAPK activation; additionally, caveolin-1 siRNA induced ASM proliferation in mitogen deficient conditions, suggesting a key role for caveolae and caveolin-1 in maintaining quiescence. Moreover, caveolin-1 accumulates twofold in myocytes induced to a contractile phenotype compared with proliferating ASM cells. Caveolin-1 siRNA failed to increase PDGF-induced p42/p44 MAPK activation and cell proliferation, however, indicating that PDGF stimulation actively reversed the antimitogenic control by caveolin-1. Notably, the PDGF induced loss of antimitogenic control by caveolin-1 coincided with a marked increase in caveolin-1 phosphorylation. Furthermore, the strong association of PDGF receptor-beta with caveolin-1 that exists in quiescent cells was rapidly and markedly reduced with agonist addition. This suggests a dynamic relationship in which mitogen stimulation actively reverses caveolin-1 suppression of p42/p44 MAPK signal transduction. As such, caveolae and caveolin-1 coordinate PDGF receptor signaling, leading to myocyte proliferation, and inhibit constitutive activity of p42/p44 MAPK to sustain cell quiescence.

Abstract-Smooth muscle cell migration in response to platelet-derived growth factor (PDGF) is a key event in several vascular pathologies, including atherosclerosis and restenosis. PDGF increases intracellular levels of reactive oxygen species (ROS) in vascular smooth muscle cells (VSMCs), but the ROS sensitivity of migration and of the signaling pathways leading to migration are largely unknown. In VSMCs, PDGF dose-dependently increased migration compared with nonstimulated cells, with a maximum increase at 10 ng/mL. Pretreatment with the antioxidant N-acetyl-cysteine, the flavin-containing enzyme inhibitor diphenylene iodonium, or the glutathione peroxidase mimetic ebselen significantly attenuated migration (PDGF alone, 5.0Ϯ1.