Imatinib Alters Agonists-mediated Cytoskeletal Biomechanics in Lung Endothelium

X. Wang, R. Bleher, L. Wang, J. G.N. Garcia, S. M. Dudek*, G. S. Shekhawat, V. P. Dravid

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The 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.

Original languageEnglish (US)
Article number14152
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Funding

This work made use of the EPIC and SPID facilities of the NUANCE Center at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. This work was supported by grants from the National Science Foundation (No. 1256188, IDBR: Development of Higher Eigenmode Ultrasound Bioprobe for Sub-Cellular Biological Imaging), National Heart Lung Blood Institute NIH grant (P01 HL 58064, R56 HL HL56088144-06A1) and National Natural Science Foundation of China (No. 31700812). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation and National Institutes of Health.

ASJC Scopus subject areas

  • General

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