Heparan Sulfate Proteoglycans Mediate Interstitial Flow Mechanotransduction Regulating MMP-13 Expression and Cell Motility via FAK-ERK in 3D CollagenReportar como inadecuado




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Background

Interstitial flow directly affects cells that reside in tissues and regulatestissue physiology and pathology by modulating important cellular processesincluding proliferation, differentiation, and migration. However, the structuresthat cells utilize to sense interstitial flow in a 3-dimensional 3D environmenthave not yet been elucidated. Previously, we have shown that interstitialflow upregulates matrix metalloproteinase MMP expression in rat vascularsmooth muscle cells SMCs and fibroblasts-myofibroblasts via activation ofan ERK1-2-c-Jun pathway, which in turn promotes cell migration in collagen.Herein, we focused on uncovering the flow-induced mechanotransduction mechanismin 3D.

Methodology-Principal Findings

Cleavage of rat vascular SMC surface glycocalyx heparan sulfate HS chainsfrom proteoglycan PG core proteins by heparinase or disruption of HS biosynthesisby silencing N-deacetylase-N-sulfotransferase1 NDST1 suppressed interstitial flow-induced ERK1-2 activation, interstitialcollagenase MMP-13 expression, and SMC motility in 3D collagen. Inhibitionor knockdown of focal adhesion kinase FAK also attenuated or blocked flow-inducedERK1-2 activation, MMP-13 expression, and cell motility. Interstitial flowinduced FAK phosphorylation at Tyr925, and this activation was blocked whenheparan sulfate proteoglycans HSPGs were disrupted. These data suggest thatHSPGs mediate interstitial flow-induced mechanotransduction through FAK-ERK.In addition, we show that integrins are crucial for mechanotransduction throughHSPGs as they mediate cell spreading and maintain cytoskeletal rigidity.

Conclusions-Significance

We propose a conceptual mechanotransduction model wherein cell surfaceglycocalyx HSPGs, in the presence of integrin-mediated cell-matrix adhesionsand cytoskeleton organization, sense interstitial flow and activate the FAK-ERKsignaling axis, leading to upregulation of MMP expression and cell motilityin 3D. This is the first study to describe a flow-induced mechanotransductionmechanism via HSPG-mediated FAK activation in 3D. This study will be of interestin understanding the flow-related mechanobiology in vascular lesion formation,tissue morphogenesis, cancer cell metastasis, and stem cell differentiationin 3D, and also has implications in tissue engineering.



Autor: Zhong-Dong Shi, Hui Wang, John M. Tarbell

Fuente: http://plos.srce.hr/



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