Loss of Endothelial CXCR7 Impairs Vascular Homeostasis, and Cardiac Remodeling After Myocardial Infarction: Implications for Cardiovascular Drug Discovery
Background—Genome-wide association studies identified the association of the CXCL12 genetic locus (which encodes the chemokine CXCL12, also known as stromal cell-derived factor 1) with coronary artery disease (CAD) and myocardial infarction (MI). Unlike CXCR4, the classical receptor for CXCL12, the function of CXCR7 (the most recently identified receptor) in vascular responses to injury and in MI remains unclear.
Methods—Tissue expression of CXCR7 was examined in arteries from mice and humans. Mice that harbored floxed CXCR7 and Cdh5-promoter driven CreERT2 were treated with tamoxifen to induce endothelial-restricted deletion of CXCR7. The resulting conditional knockout mice and littermate controls were studied for arterial response to angioplasty wire-injury and cardiac response to coronary artery ligation. The role of CXCR7 in endothelial cell proliferation and angiogenesis was determined in vitro using cells from mice and humans. The effects of adenoviral delivery of CXCR7 gene and pharmacological activation of CXCR7 were evaluated in mice subjected to MI.
Results—Injured arteries from both humans and mice exhibited endothelial CXCR7 expression. Conditional endothelial CXCR7 deletion promoted neointimal formation without altering plasma lipid levels following endothelial injury, and also exacerbated heart functional impairment following MI, with increased both mortality and infarct sizes. Mechanistically, the exacerbated responses in vascular and cardiac remodeling are attributable to the key role of CXCR7 in promoting endothelial proliferation and angiogenesis. Impressively, the impaired post-MI cardiac remodeling occurred with elevated levels of CXCL12, which was previously thought to mediate cardiac protection by exclusively engaging its cognate receptor, CXCR4. Additionally, CXCR7 gene delivery via left ventricular injection, or treatment with a CXCR7 agonist, both offered cardiac protection after MI.
Conclusions—CXCR7 represents a novel regulator of vascular homeostasis that functions in the endothelial compartment, with sufficient capacity to impact cardiac function and remodeling following MI. Activation of CXCR7 may have therapeutic potential for clinical restenosis after percutaneous coronary intervention and for heart remodeling after MI.
- Drug discovery
- endothelial cell
- cardiovascular disease
- vascular remodeling
- myocardial infarction
- Received April 18, 2016.
- Revision received January 18, 2017.
- Accepted January 24, 2017.