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, Jahrgang 22, Nr. 11, 5908, 31.05.2021.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -