Micro-RNA Regulated Pro-Angiogenic Signaling in Arteriovenous Loops in Patients with Combined Vascular and Soft Tissue Reconstructions – Reisiting the Nutrient Flap Concept

Background: The placement of arteriovenous (AV) loops can enable microvascular anastomoses of free flaps when recipient vessels are scarce. In animal models, elevated fluid shear stress in AV loops promotes neoangiogenesis. Anecdotal reports in patients indicate that vein grafts used in free flap reconstructions of ischemic lower extremities are able to induce capillary formation. However, flow-stimulated angiogenesis has never been systematically investigated in humans and it is unclear whether shear stress alters proangiogenic signaling pathways within the vascular wall of human AV loops. Methods: Eight patients with lower extremity soft tissue defects underwent two-stage reconstructions with AV loop placements, and free flap anastomoses to the loops 10-14 days later. MicroRNA and gene expression profiles were determined in tissue samples harvested from vein grafts of AV loops by microarray analysis and quantitative real time polymerase chain reaction. Samples from untreated veins served as controls. Results: A strong deregulation of microRNA and gene expression was detected in AV loops, showing an overexpression of angiopoetic cytokines, oxygenation associated genes, vascular growth factors, as well as connexin-43. We discovered inverse correlations and validated as well as bioinformatically predicted interactions between angiogenesis regulating genes and microRNAs in AV loops. Conclusion: Our findings demonstrate that elevated shear stress triggers pro-angiogenic signaling pathways in human venous tissue, indicating that AV loops may have the ability to induce neoangiogenesis in humans. Our data corroborate the nutrient flap hypothesis and provide a molecular background for AV loop based tissue engineering with potential clinical applications for soft tissue defect reconstruction. * These authors contributed equally to this work. Financial Disclosure Statement: The authors have no financial disclosures : The funding of this study was solely institutional. Acknowledgements: The authors thank Dr. Matthias Schulte for excellent technical support. Corresponding author: Dominic Henn, MD, Department of Hand, Plastic and Reconstructive Surgery, BG Trauma Center Ludwigshafen, Department of Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Str. 13, 67071 Ludwigshafen, Germany. tel: +49-621-6810-8953, email: dominic.henn@bgu-ludwigshafen.de ©2018American Society of Plastic Surgeons

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