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Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy

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Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy. / Ghadge, Santhosh Kumar; Messner, Moritz; Seiringer, Herbert; Maurer, Thomas; Staggl, Simon; Zeller, Tanja; Müller, Christian; Börnigen, Daniela; Weninger, Wolfgang J; Geyer, Stefan H; Sopper, Sieghart; Krogsdam, Anne; Pölzl, Gerhard; Bauer, Axel; Zaruba, Marc-Michael.

In: INT J MOL SCI, Vol. 22, No. 11, 5908, 31.05.2021.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ghadge, SK, Messner, M, Seiringer, H, Maurer, T, Staggl, S, Zeller, T, Müller, C, Börnigen, D, Weninger, WJ, Geyer, SH, Sopper, S, Krogsdam, A, Pölzl, G, Bauer, A & Zaruba, M-M 2021, 'Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy', INT J MOL SCI, vol. 22, no. 11, 5908. https://doi.org/10.3390/ijms22115908

APA

Ghadge, S. K., Messner, M., Seiringer, H., Maurer, T., Staggl, S., Zeller, T., Müller, C., Börnigen, D., Weninger, W. J., Geyer, S. H., Sopper, S., Krogsdam, A., Pölzl, G., Bauer, A., & Zaruba, M-M. (2021). Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy. INT J MOL SCI, 22(11), [5908]. https://doi.org/10.3390/ijms22115908

Vancouver

Ghadge SK, Messner M, Seiringer H, Maurer T, Staggl S, Zeller T et al. Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy. INT J MOL SCI. 2021 May 31;22(11). 5908. https://doi.org/10.3390/ijms22115908

Bibtex

@article{bd2469c0f39644df964dda63de04083d,
title = "Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy",
abstract = "The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12-/-). SM-CXCL12-/- mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12-/- mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12-/- mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.",
keywords = "Ablation Techniques, Animals, Cardiomegaly/genetics, Chemokine CXCL12/genetics, Coronary Vessels, Disease Models, Animal, Gene Expression Regulation/genetics, Humans, Macrophages/metabolism, Mice, Muscle, Smooth/metabolism, Myocardial Infarction/genetics, Myocardium/metabolism, Receptors, CXCR/genetics",
author = "Ghadge, {Santhosh Kumar} and Moritz Messner and Herbert Seiringer and Thomas Maurer and Simon Staggl and Tanja Zeller and Christian M{\"u}ller and Daniela B{\"o}rnigen and Weninger, {Wolfgang J} and Geyer, {Stefan H} and Sieghart Sopper and Anne Krogsdam and Gerhard P{\"o}lzl and Axel Bauer and Marc-Michael Zaruba",
year = "2021",
month = may,
day = "31",
doi = "10.3390/ijms22115908",
language = "English",
volume = "22",
journal = "INT J MOL SCI",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "11",

}

RIS

TY - JOUR

T1 - Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy

AU - Ghadge, Santhosh Kumar

AU - Messner, Moritz

AU - Seiringer, Herbert

AU - Maurer, Thomas

AU - Staggl, Simon

AU - Zeller, Tanja

AU - Müller, Christian

AU - Börnigen, Daniela

AU - Weninger, Wolfgang J

AU - Geyer, Stefan H

AU - Sopper, Sieghart

AU - Krogsdam, Anne

AU - Pölzl, Gerhard

AU - Bauer, Axel

AU - Zaruba, Marc-Michael

PY - 2021/5/31

Y1 - 2021/5/31

N2 - The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12-/-). SM-CXCL12-/- mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12-/- mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12-/- mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

AB - The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12-/-). SM-CXCL12-/- mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12-/- mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12-/- mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

KW - Ablation Techniques

KW - Animals

KW - Cardiomegaly/genetics

KW - Chemokine CXCL12/genetics

KW - Coronary Vessels

KW - Disease Models, Animal

KW - Gene Expression Regulation/genetics

KW - Humans

KW - Macrophages/metabolism

KW - Mice

KW - Muscle, Smooth/metabolism

KW - Myocardial Infarction/genetics

KW - Myocardium/metabolism

KW - Receptors, CXCR/genetics

U2 - 10.3390/ijms22115908

DO - 10.3390/ijms22115908

M3 - SCORING: Journal article

C2 - 34072818

VL - 22

JO - INT J MOL SCI

JF - INT J MOL SCI

SN - 1661-6596

IS - 11

M1 - 5908

ER -