The role of microRNAs during arteriogenesis

• Applicants: Dr. Silvia Fischer; Dr. Kerstin Troidl
• Subject Area: General and Visceral Surgery
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253160555

The fluid shear stress (FSS)-induced remodeling of pre-existing collateral arterioles into fully functional conductance arteries is termed "arteriogenesis".It has been shown that FFS, which is exerted on endothelial cells, leads to changes in the expression profile of microRNA (miRs), which in turn alters morphology as well as function of endothelial cells under flow conditions. miRs are small non-conding RNAs, which regulate gene expression post-transcriptionally either through inhibition of translation or due to RNA decay. In a pilot study we identified a differential expression of miR-24, miR-143, miR-146a and miR-195 in growing collateral arteries by microarray screening, quantitative RT-PCR, and in situ hybridization.Through the current project the relevance of these miRs for arteriogenesis will be evaluated in vitro and in a mouse model. In preliminary experiments, blockage of those miRs by local intra-arterial injection of antimiRs (single-standed complementary RNA oligonucleotides) after ligation of the femoral artery showed that mice, which were treated with antimiR-143, have a significantly reduced perfusion recovery. In addition they suffer from increased necrosis and autoamputation of hind limbs, which results in a higher lethality. While elucidating the cause of the drastic consequences of antimiR-143 application, the possibility of mir-143 being a key regulator and the presence of unwanted side effects of therapeutic miRNA modulation will be accounted for. The present study will clarify the differentiation between specific antimiR effects (blockage of target mRNA) during collateral growth and unspecific systemic antimiR effects. On one hand, the regulation and molecular interaction of miRNAs and their contribution to arteriogenic key processes will be assessed, on the other hand, possible influence of antimiR application on vascular hemostasis will be examined. It has been shown that ribonucleases are not inert structures; they rather display toxic, apoptotic pro-coagulatory or pro-inflammatory activity. It will be analyzed in detail if this is also true for antimiRs.

• DFG Programme: Research Grants