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.

A CXCL12 morphogen gradient uncovers lung endothelial heterogeneity and promotes distal vascular growth

“…At several stages, we confirmed specificity of the reporter using immunohistochemistry (IHC) for DsRed reporter expression and markers for endothelium including ETS related gene (ERG) and endomucin (EMCN). As in other organ systems, Cxcl12-DsRed is expressed highly throughout the arterial endothelium with additional expression observed in vascular smooth muscle cells (VSMCs) (Fig S1A-F) (Chang et al, 2017;Ghadge et al, 2021;Ivins et al, 2015;Takabatake et al, 2009). We observed no DsRed expression in vein endothelium during these developmental time periods.…”

Emerging Roles of the Atypical Chemokine Receptor 3 (ACKR3) in Cardiovascular Diseases

“…Interestingly, this phenotype was associated with downregulation of ACKR3 expression in coronary artery endothelial cells, indicating an important role of ACKR3 in vessel maturation and cardiac remodelling. Furthermore, treatment of these mice with ACKR3 agonist TC14012 attenuated these defects and restored cardiac function with a marked activation of pERK signalling, suggesting that activation of pERK signalling pathways induced by the binding of TC14012 to ACKR3 prevented the progression of cardiac hypertrophy ( 67 ) ( Figure 1 ).…”

“…More recently, conditional smooth muscle specific deficiency of Cxcl12 (SM22CRE- Cxcl12 flox/flox ) revealed that CXCL12 was involved in cardiac and vascular homeostasis by regulating ACKR3 expression and its signalling. Indeed, in these mice, a high embryonic lethality characterized by developmental defects of the cardiovascular system was observed concomitant with alterations of coronary arteries structure ( 67 ). Adult mice developed cardiac hypertrophy and severe vascular defects associated with increased fibrosis, apoptosis and dilated arteries with thinner walls leading to impaired cardiac function.…”

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

“…However, pharmacological targeting of ACKR3/CXCR7 by administration of CXCR7-agonist TC14012 retards cardiac hypertrophy in these mice, suggesting its therapeutic efficacy in counteracting adverse remodeling. TC14012-treated SM22α-Cre + CXCL12 f/f mice also show improvements in LVEF [ 132 ].…”