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Upregulation of Proangiogenic miRNAs and Genes from the EGF Receptor and Angiopoietin Families in Arteriovenous Loops in Patients with Microsurgical Lower Extremity Reconstruction
Dominic Henn, MD1, Masood Abu-Halima, PhD2, Florian Falkner, BS1, Dominik Wermke, MS2, Enikö J. Manz, MD3, Amelia Schäfer, MD3, Clemens Kühner, MD3, Andreas Keller, PhD2, Thomas Kremer, MD1, Frederick J. Hernekamp, MD1, Eckart Meese, PhD2, Volker J. Schmidt, MD1, Ulrich Kneser, MD1.
1Heidelberg University, BG Trauma Center Ludwigshafen, Ludwigshafen, Germany, 2Saarland University, Homburg, Germany, 3Ludwigshafen Medical Center, Ludwigshafen, Germany.

PURPOSE: A lack of recipient vessels for microsurgical extremity reconstructions may result from peripheral vascular disease, trauma, or oncologic resections and can be managed by vascular reconstructions with arteriovenous (AV) loops, which serve as recipient vessels for free flap anastomoses. In small and large animal models AV loops promote angiogenesis, presumably through elevated shear stress on the vascular endothelium. It has been postulated that vascularized free flaps are able to induce angiogenesis in ischemic lower extremities of patients with peripheral vascular disease, however, the molecular basis of this “nutrient flap” concept has never been examined in a clinical setting. In this study we analyzed miRNA and gene expression profiles in AV loops from patients with combined vascular and soft-tissue reconstructions in order to investigate whether enhanced blood flow in an AV loop leads to an upregulation of proangiogenic miRNAs and genes in humans.
METHODS: Eight patients with lower extremity soft-tissue defects and insufficient recipient vessels underwent two-stage vascular and soft-tissue reconstructions. AV loops were created to provide recipient vessels for microvascular anastomoses of free flaps, which were performed 10-14 days later. Tissue samples were collected from the vein grafts of the AV loops upon free flap anastomoses. The expression levels of 2,549 miRNAs and 26,083 genes were examined by microarray analysis and selectively confirmed by quantitative real time polymerase chain reaction. Samples from 8 untreated saphenous veins served as controls.
RESULTS: Hierarchical clustering exhibited a clear separation of the examined groups in both miRNA and gene expression profiles. 14 miRNAs and 3,213 genes were significantly upregulated, whereas 31 mRNAs and 2,913 genes were significantly downregulated in samples from AV loops compared to untreated veins. A marked upregulation of pro-angiogenetic miRNAs and genes was observed in samples from AV loops compared to controls: miR-143-5p, miR-145-3p, miR-145-5p, and miR-133b, which promote angiogenesis were upregulated by a > 4-fold change (p < 0.05). Moreover, comparison of gene expression in AV loops with controls revealed an upregulation of key factors of angiogenesis from the EGF receptor family (ErbB-1, Erb-B2, Erb-B4), the angiopoietin family (ANGPT1, ANGPTL1, ANGPTL5, ANGPTL7) as well as of VEGFB, FGFR2, WNT11, and SMAD4 (p < 0.05, > 1.8-fold change).
CONCLUSION: Proangiogenic miRNAs and genes, in particular from the EGF receptor and angiopoietin families, are significantly upregulated in AV loops after exposure to increased blood flow for 10-14 days. These findings corroborate the
“nutrient flap” hypothesis and indicate that combined vascular and microsurgical soft-tissue reconstructions likely exert beneficial influence on the perfusion of ischemic lower extremities in patients with peripheral vascular disease due to an upregulation of proangiogenic factors within the reconstructed vasculature. Our data moreover provide possible targets for future molecular therapeutic strategies to improve the perfusion of ischemic tissue.


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