Imatinib Alters Agonists-mediated Cytoskeletal Biomechanics in Lung Endothelium
AffiliationUniv Arizona, Dept Med
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PublisherNATURE PUBLISHING GROUP
CitationImatinib Alters Agonists-mediated Cytoskeletal Biomechanics in Lung Endothelium 2017, 7 (1) Scientific Reports
Rights© The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.
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AbstractThe endothelium serves as a size-selective barrier and tightly controls the fluid exchange from the circulation to the surrounding tissues. In this study, a multiplexed microscopy characterization is developed to study the spatio-temporal effects of Abl kinases on endothelial cytoskeletal structure using AFM, SEM, and immunofluorescence. Sphingosine 1-phosphate (S1P) produces significant endothelial barrier enhancement by means of peripheral actin rearrangement. However, Abl kinase inhibition by imatinib reduces rapid redistribution of the important cytoskeletal proteins to the periphery and their association with the cortical actin ring. Herein, it moderates the thickness of the cortical actin ring, and diminishes the increase in elastic modulus at the periphery and cytoplasm. These findings demonstrate that imatinib attenuates multiple cytoskeletal changes associated with S1P-mediated endothelial barrier enhancement and suggest a novel role for Abl kinases in mediating these S1P effects. These observations bridge the gap between molecule dynamics, structure complexity and function connectivity across varied length-scales to improve our understanding on human pulmonary endothelial barrier regulation. Moreover, our study suggests a framework for understanding form-function relationships in other biomechanical subsystems, wherein complex hierarchical organization programmed from the molecular scale to the cellular and tissue levels has an intimate relationship to the overall physiological function.
VersionFinal published version
SponsorsSoft and Hybrid Nanotechnology Experimental (SHyNE) Resource [NSF NNCI-1542205]; MRSEC program at the Materials Research Center [NSF DMR-1121262]; International Institute for Nanotechnology (IIN); Keck Foundation; State of Illinois, through the IIN; National Science Foundation ; National Heart Lung Blood Institute NIH grant [P01 HL 58064, R56 HL HL56088144-06A1]; National Natural Science Foundation of China 
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