The chemokine receptor CXCR7 functions to regulate cardiac valve remodeling.
CXCR7 (RDC1), a G-protein-coupled receptor with conserved motifs characteristic of chemokine receptors, is enriched in endocardial and cushion mesenchymal cells in developing hearts, but its function is unclear. Cxcr7 germline deletion resulted in perinatal lethality with complete penetrance. Mutant embryos exhibited aortic and pulmonary valve stenosis due to semilunar valve thickening, with occasional ventricular septal defects. Semilunar valve mesenchymal cell proliferation increased in mutants from embryonic day 14 onward, but the cell death rate remained unchanged. Cxcr7 mutant valves had increased levels of phosphorylated Smad1/5/8, indicating increased BMP signaling, which may partly explain the thickened valve leaflets. The hyperproliferative phenotype appeared to involve Cxcr7 function in endocardial cells and their mesenchymal derivatives, as Tie2-Cre Cxcr7(flox/-) mice had semilunar valve stenosis. Thus, CXCR7 is involved in semilunar valve development, possibly by regulating BMP signaling, and may contribute to aortic and pulmonary valve stenosis.
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
Sangho
S
Yu
Dianna
D
Crawford
Takatoshi
T
Tsuchihashi
Timothy W
TW
Behrens
Deepak
D
Srivastava
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004699:Endocardium / Q000166:cytology; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology*; D006346:Heart Septum / Q000473:pathology; D006349:Heart Valve Diseases / Q000473:pathology; D006351:Heart Valves / Q000166:cytology / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology*; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038081:Organogenesis; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D019485:Bone Morphogenetic Proteins; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled
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