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

International Journal of Molecular Sciences

Daniela Börnigen¹  Christian Müller¹  Tanja Zeller¹  SanthoshKumar Ghadge²  Simon Staggl²  Gerhard Pölzl²  Marc-Michael Zaruba²  Herbert Seiringer²  Moritz Messner²  Axel Bauer²  Thomas Maurer²  Sieghart Sopper³  WolfgangJ. Weninger⁴  StefanH. Geyer⁴  Anne Krogsdam⁵ 

[1] Clinic for Cardiology, Medical University Center Hamburg-Eppendorf, University Heart and Vascular Center Hamburg, 20251 Hamburg, Germany;Department of Internal Medicine III, Cardiology and Angiology, Medical University Innsbruck, 6020 Innsbruck, Austria;Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria;Division of Anatomy & MIC, Medical University of Vienna, 1090 Vienna, Austria;Division of Bioinformatics, Medical University Innsbruck, Biocenter, 6020 Innsbruck, Austria;

关键词: CXCL12;    cardiac hypertrophy;    fibrosis;    remodeling;    M2 macrophages;    coronary artery;   

DOI  :  10.3390/ijms22115908

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown