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Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle.

Abstract：

AIMS:Shock wave therapy (SWT) represents a clinically widely used angiogenic and thus regenerative approach for the treatment of ischaemic heart or limb disease. Despite promising results in preclinical and clinical trials, the exact mechanism of action remains unknown. Toll-like receptor 3, which is part of the innate immunity, is activated by binding double-stranded (ds) RNA. It plays a key role in inflammation, a process that is needed also for angiogenesis. We hypothesize that SWT causes cellular cavitation without damaging the target cells, thus liberating cytoplasmic RNA that in turn activates TLR3. METHODS AND RESULTS:SWT induces TLR3 and IFN-β1 gene expression as well as RNA liberation from endothelial cells in a time-dependant manner. Conditioned medium from SWT-treated HUVECs induced TLR3 signalling in reporter cells. The response was lost when the medium was treated with RNase III to abolish dsRNAs or when TLR3 was silenced using siRNAs. In a mouse hind limb ischaemia model using wt and TLR3(-/-) mice (n = 6), SWT induced angiogenesis and arteriogenesis only in wt animals. These effects were accompanied by improved blood perfusion of treated limbs. Analysis of main molecules of the TLR3 pathways confirmed TLR3 signalling in vivo following SWT. CONCLUSION:Our data reveal a central role of the innate immune system, namely Toll-like receptor 3, to mediate angiogenesis upon release of cytoplasmic RNAs by mechanotransduction of SWT.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Holfeld J,Tepeköylü C,Reissig C,Lobenwein D,Scheller B,Kirchmair E,Kozaryn R,Albrecht-Schgoer K,Krapf C,Zins K,Urbschat A,Zacharowski K,Grimm M,Kirchmair R,Paulus P

doi

10.1093/cvr/cvv272

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

331-43

issue

2

eissn

0008-6363

issn

1755-3245

pii

cvv272

journal_volume

109

pub_type

杂志文章

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