Franziska Pankratz1, Xavier Bemtgen1, Robert Zeiser1, Franziska Leonhardt1, Sheena Kreuzaler1, Ingo Hilgendorf1, Christian Smolka1, Thomas Helbing1, Imo Hoefer1, Jennifer S Esser1, Max Kustermann1, Martin Moser1, Christoph Bode1, Sebastian Grundmann2. 1. From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.). 2. From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.). sebastian.grundmann@universitaets-herzzentrum.de.
Abstract
BACKGROUND: Adaptive neovascularization after arterial occlusion is an important compensatory mechanism in cardiovascular disease and includes both the remodeling of pre-existing vessels to collateral arteries (arteriogenesis) and angiogenic capillary growth. We now aimed to identify regulatory microRNAs involved in the modulation of neovascularization after femoral artery occlusion in mice. METHODS AND RESULTS: Using microRNA-transcriptome analysis, we identified miR-155 as a downregulated microRNA during hindlimb ischemia. Correspondingly, inhibition of miR-155 in endothelial cells had a stimulatory effect on proliferation and angiogenic tube formation via derepression of its direct target gene angiotensin II type 1 receptor. Surprisingly, miR-155-deficient mice showed an unexpected phenotype in vivo, with a strong reduction of blood flow recovery after femoral artery ligation (arteriogenesis) dependent on the attenuation of leukocyte-endothelial interaction and a reduction of proarteriogenic cytokine expression. Consistently, miR-155-deficient macrophages exhibit a specific alteration of the proarteriogenic cytokine expression profile, which is partly mediated by the direct miR-155 target gene SOCS-1. CONCLUSIONS: Our data demonstrate that miR-155 exerts an antiangiogenic but proarteriogenic function in the regulation of neovascularization via the suppression of divergent cell-specific target genes and that its expression in both endothelial and bone marrow-derived cells is essential for arteriogenesis in response to hindlimb ischemia in mice.
BACKGROUND: Adaptive neovascularization after arterial occlusion is an important compensatory mechanism in cardiovascular disease and includes both the remodeling of pre-existing vessels to collateral arteries (arteriogenesis) and angiogenic capillary growth. We now aimed to identify regulatory microRNAs involved in the modulation of neovascularization after femoral artery occlusion in mice. METHODS AND RESULTS: Using microRNA-transcriptome analysis, we identified miR-155 as a downregulated microRNA during hindlimb ischemia. Correspondingly, inhibition of miR-155 in endothelial cells had a stimulatory effect on proliferation and angiogenic tube formation via derepression of its direct target gene angiotensin II type 1 receptor. Surprisingly, miR-155-deficient mice showed an unexpected phenotype in vivo, with a strong reduction of blood flow recovery after femoral artery ligation (arteriogenesis) dependent on the attenuation of leukocyte-endothelial interaction and a reduction of proarteriogenic cytokine expression. Consistently, miR-155-deficient macrophages exhibit a specific alteration of the proarteriogenic cytokine expression profile, which is partly mediated by the direct miR-155 target gene SOCS-1. CONCLUSIONS: Our data demonstrate that miR-155 exerts an antiangiogenic but proarteriogenic function in the regulation of neovascularization via the suppression of divergent cell-specific target genes and that its expression in both endothelial and bone marrow-derived cells is essential for arteriogenesis in response to hindlimb ischemia in mice.
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312
Authors: Jesús García-Donas; Benoit Beuselinck; Lucía Inglada-Pérez; Osvaldo Graña; Patrick Schöffski; Agnieszka Wozniak; Oliver Bechter; Maria Apellániz-Ruiz; Luis Javier Leandro-García; Emilio Esteban; Daniel E Castellano; Aranzazu González Del Alba; Miguel Angel Climent; Susana Hernando; José Angel Arranz; Manuel Morente; David G Pisano; Mercedes Robledo; Cristina Rodriguez-Antona Journal: JCI Insight Date: 2016-07-07