MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization

Franziska Pankratz; Xavier Bemtgen; Robert Zeiser; Franziska Leonhardt; Sheena Kreuzaler; Ingo Hilgendorf; Christian Smolka; Thomas Helbing; IE Höfer; Jennifer S Esser; Max Kustermann; Martin Moser; Christoph Bode; Sebastian Grundmann

doi:10.1161/CIRCULATIONAHA.114.014579

MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization

Franziska Pankratz, Xavier Bemtgen, Robert Zeiser, Franziska Leonhardt, Sheena Kreuzaler, Ingo Hilgendorf, Christian Smolka, Thomas Helbing, IE Höfer, Jennifer S Esser, Max Kustermann, Martin Moser, Christoph Bode, Sebastian Grundmann

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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.

Original language	English
Pages (from-to)	1575-1589
Number of pages	15
Journal	Circulation
Volume	131
Issue number	18
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.114.014579
Publication status	Published - 2015

Keywords

Animals
Arteries
Base Sequence
Cell Movement
Collateral Circulation
Cytokines
Down-Regulation
Endothelium, Vascular
Femoral Artery
Gene Expression Regulation
Hindlimb
Human Umbilical Vein Endothelial Cells
Intercellular Signaling Peptides and Proteins
Ischemia
Laser-Doppler Flowmetry
Leukocytes
Ligation
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs
Molecular Sequence Data
Neovascularization, Physiologic
Receptor, Angiotensin, Type 1
Suppressor of Cytokine Signaling Proteins

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10.1161/CIRCULATIONAHA.114.014579

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Pankratz, F., Bemtgen, X., Zeiser, R., Leonhardt, F., Kreuzaler, S., Hilgendorf, I., Smolka, C., Helbing, T., Höfer, IE., Esser, J. S., Kustermann, M., Moser, M., Bode, C., & Grundmann, S. (2015). MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization. Circulation, 131(18), 1575-1589. https://doi.org/10.1161/CIRCULATIONAHA.114.014579

@article{810f7fc8c97d4680ae4862762769224d,

title = "MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization",

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.",

keywords = "Animals, Arteries, Base Sequence, Cell Movement, Collateral Circulation, Cytokines, Down-Regulation, Endothelium, Vascular, Femoral Artery, Gene Expression Regulation, Hindlimb, Human Umbilical Vein Endothelial Cells, Intercellular Signaling Peptides and Proteins, Ischemia, Laser-Doppler Flowmetry, Leukocytes, Ligation, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs, Molecular Sequence Data, Neovascularization, Physiologic, Receptor, Angiotensin, Type 1, Suppressor of Cytokine Signaling Proteins",

author = "Franziska Pankratz and Xavier Bemtgen and Robert Zeiser and Franziska Leonhardt and Sheena Kreuzaler and Ingo Hilgendorf and Christian Smolka and Thomas Helbing and IE H{\"o}fer and Esser, \{Jennifer S\} and Max Kustermann and Martin Moser and Christoph Bode and Sebastian Grundmann",

note = "{\textcopyright} 2015 American Heart Association, Inc.",

year = "2015",

doi = "10.1161/CIRCULATIONAHA.114.014579",

language = "English",

volume = "131",

pages = "1575--1589",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams \& Wilkins",

number = "18",

}

Pankratz, F, Bemtgen, X, Zeiser, R, Leonhardt, F, Kreuzaler, S, Hilgendorf, I, Smolka, C, Helbing, T, Höfer, IE, Esser, JS, Kustermann, M, Moser, M, Bode, C & Grundmann, S 2015, 'MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization', Circulation, vol. 131, no. 18, pp. 1575-1589. https://doi.org/10.1161/CIRCULATIONAHA.114.014579

TY - JOUR

T1 - MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization

AU - Pankratz, Franziska

AU - Bemtgen, Xavier

AU - Zeiser, Robert

AU - Leonhardt, Franziska

AU - Kreuzaler, Sheena

AU - Hilgendorf, Ingo

AU - Smolka, Christian

AU - Helbing, Thomas

AU - Höfer, IE

AU - Esser, Jennifer S

AU - Kustermann, Max

AU - Moser, Martin

AU - Bode, Christoph

AU - Grundmann, Sebastian

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Animals

KW - Arteries

KW - Base Sequence

KW - Cell Movement

KW - Collateral Circulation

KW - Cytokines

KW - Down-Regulation

KW - Endothelium, Vascular

KW - Femoral Artery

KW - Gene Expression Regulation

KW - Hindlimb

KW - Human Umbilical Vein Endothelial Cells

KW - Intercellular Signaling Peptides and Proteins

KW - Ischemia

KW - Laser-Doppler Flowmetry

KW - Leukocytes

KW - Ligation

KW - Macrophages

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - MicroRNAs

KW - Molecular Sequence Data

KW - Neovascularization, Physiologic

KW - Receptor, Angiotensin, Type 1

KW - Suppressor of Cytokine Signaling Proteins

U2 - 10.1161/CIRCULATIONAHA.114.014579

DO - 10.1161/CIRCULATIONAHA.114.014579

M3 - Article

C2 - 25850724

SN - 0009-7322

VL - 131

SP - 1575

EP - 1589

JO - Circulation

JF - Circulation

IS - 18

ER -

MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization

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Keywords

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