A Swine Hind Limb Ischemia Model Useful for Testing Peripheral Artery Disease Therapeutics

• Type of Material: Article
• Authors: Juline N Deppen, Georgia Institute of Technology; Sydney C Ginn, Georgia Institute of Technology; Na Hee Kim, Emory University; Lanfang Wang, Emory University; Ronald Voll, Emory University; Steven H Liang, Massachusetts General Hospital and Harvard Medical School; Mark Goodman, Emory University; John Oshinski, Emory University; Rebecca Levit, Emory University
• Language: English
• Date: 2021-05-28
• Publisher: SPRINGER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer Science Business Media, LLC, part of Springer Nature
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s12265-021-10134-8
• Title of Journal or Parent Work: JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
• Volume: 14
• Issue: 6
• Start Page: 1186
• End Page: 1197
• Grant/Funding Information: These data were generated with support of the Aronov Foundation, the Emory University Center for Systems Imaging Pilot Funding, the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under Award Numbers UL1TR002378 and TL1TR002382 (J.N.D), and R01HL140223 (R.D.L.). Experiments were performed in part using the Microscopy in Medicine Core (NIH grant P01HL095070) and the Emory Integrated Genomics Core (subsidized by the Emory University School of Medicine and additionally supported by NIH Award Number UL1TR002378). The content is solely the responsibility of the authors and does not necessarily represent the views of NIH.
• Keywords: Science & Technology; Life Sciences & Biomedicine; RADIOFLUORINATION; Cardiac & Cardiovascular Systems; BLOOD-FLOW; CELL THERAPY; Ischemia; Function; GROWTH; COLONY-STIMULATING FACTOR; Cell; Limb; Peripheral artery disease; PIG MODEL; Medicine, Research & Experimental; Muscle; Research & Experimental Medicine; Cardiovascular System & Cardiology; Perfusion; Swine; ARTERIOGENESIS; LIGATION; GENE-THERAPY; PERFUSION

Abstract

Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations. Hyperemia-dependent muscle perfusion deficits, depressed limb blood pressure, arteriogenesis, muscle atrophy, and microscopic myopathy were quantifiable in ischemic limbs 6 weeks post-ligation. Porcine mesenchymal stromal cells (MSCs) engineered to express a reporter gene were visualized post-administration via positron emission tomography (PET) in vivo. These results establish a preclinical platform enabling better optimization of PAD therapies, including cellular therapeutics, increasing bench-to-bedside translational success. Graphical abstract: [Figure not available: see fulltext.].