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Cyclic mechanical reinforcement of integrin-ligand interactions.

ABSTRACT: Cells regulate adhesion in response to internally generated and externally applied forces. Integrins connect the extracellular matrix to the cytoskeleton and provide cells with mechanical anchorages and signaling platforms. Here we show that cyclic forces applied to a fibronectin-integrin ?5?1 bond switch the bond from a short-lived state with 1 s lifetime to a long-lived state with 100 s lifetime. We term this phenomenon "cyclic mechanical reinforcement," as the bond strength remembers the history of force application and accumulates over repeated cycles, but does not require force to be sustained. Cyclic mechanical reinforcement strengthens the fibronectin-integrin ?5?1 bond through the RGD binding site of the ligand with the synergy binding site greatly facilitating the process. A flexible integrin hybrid domain is also important for cyclic mechanical reinforcement. Our results reveal a mechanical regulation of receptor-ligand interactions and identify a molecular mechanism for cell adhesion strengthening by cyclic forces.

SUBMITTER: Kong F

PROVIDER: S-EPMC3615084 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Cyclic mechanical reinforcement of integrin-ligand interactions.

Kong Fang F Li Zhenhai Z Parks William M WM Dumbauld David W DW García Andrés J AJ Mould A Paul AP Humphries Martin J MJ Zhu Cheng C

Molecular cell 20130214 6

Cells regulate adhesion in response to internally generated and externally applied forces. Integrins connect the extracellular matrix to the cytoskeleton and provide cells with mechanical anchorages and signaling platforms. Here we show that cyclic forces applied to a fibronectin-integrin α5β1 bond switch the bond from a short-lived state with 1 s lifetime to a long-lived state with 100 s lifetime. We term this phenomenon "cyclic mechanical reinforcement," as the bond strength remembers the hist ...[more]

PMID: 23416109

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Project description:OBJECTIVES:Positive pressure ventilation exposes the lung to mechanical stresses that can exacerbate injury. The exact mechanism of this pathologic process remains elusive. The goal of this study was to describe recruitment/derecruitment at acinar length scales over short-time frames and test the hypothesis that mechanical interdependence between neighboring lung units determines the spatial and temporal distributions of recruitment/derecruitment, using a computational model. DESIGN:Experimental animal study. SETTING:International synchrotron radiation laboratory. SUBJECTS:Four anesthetized rabbits, ventilated in pressure controlled mode. INTERVENTIONS:The lung was consecutively imaged at ~ 1.5-minute intervals using phase-contrast synchrotron imaging, at positive end-expiratory pressures of 12, 9, 6, 3, and 0 cm H2O before and after lavage and mechanical ventilation induced injury. The extent and spatial distribution of recruitment/derecruitment was analyzed by subtracting subsequent images. In a realistic lung structure, we implemented a mechanistic model in which each unit has individual pressures and speeds of opening and closing. Derecruited and recruited lung fractions (Fderecruited, Frecruited) were computed based on the comparison of the aerated volumes at successive time points. MEASUREMENTS AND MAIN RESULTS:Alternative recruitment/derecruitment occurred in neighboring alveoli over short-time scales in all tested positive end-expiratory pressure levels and despite stable pressure controlled mode. The computational model reproduced this behavior only when parenchymal interdependence between neighboring acini was accounted for. Simulations closely mimicked the experimental magnitude of Fderecruited and Frecruited when mechanical interdependence was included, while its exclusion gave Frecruited values of zero at positive end-expiratory pressure greater than or equal to 3?cm H2O. CONCLUSIONS:These findings give further insight into the microscopic behavior of the injured lung and provide a means of testing protective-ventilation strategies to prevent recruitment/derecruitment and subsequent lung damage.

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Cyclic mechanical reinforcement of integrin-ligand interactions.

Publications

Cyclic mechanical reinforcement of integrin-ligand interactions.

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