The Chemokine Receptor CXCR7 Functions in Endocardial-Derived Cells to Regulate Cardiac Valve Remodeling

Date

2010-01-12

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Abstract

Cardiac disease is the number one killer in developed countries and congenital heart diseases are the most common birth defects worldwide. The heart supplies nutrients and oxygen to the entire body, therefore the proper development and function of the heart is essential for survival of an organism. During looping and maturation phases of heart development, proper separation of the outflow tract and chambers, and correct connection to the existing vascular system are critical to ensure unidirectional blood flow and supply of oxygenated blood to the rest of the body. Cardiac neural crest cells and endocardial cushions contribute significantly to these remodeling processes. Cardiac valves are fibrous tissues that separate atria from ventricles and ventricles from great vessels, and allow unidirectional blood flow through the heart. They are derived from specific sets of endocardial cells in the outflow tract and atrioventricular canal. Cardiac valvulogenesis is a highly ordered process and small perturbations in any of signaling pathways involved can result in fatal consequences. As a result, cardiac valve anomaly is one of the most common congenital heart diseases. CXCR7 is a chemokine receptor whose function in the heart is unknown. Unexpected cardiac phenotypes of Cxcr7 knockout mice prompted further investigation to elucidate its role during heart development. I speculated that CXCR7 functions during cardiac valve formation due to its high expression in cushion endocardial and mesenchymal cells, and the phenotype of Cxcr7 knockout mice at birth: cyanotic pups and enlarged hearts. Histological analysis of Cxcr7 knockout hearts at different developmental stages revealed that the aortic and pulmonary valves were thickened during late valve remodeling. This was due to unchecked proliferation of cushion mesenchymal cells as revealed by phospho-histone H3 staining. Increased proliferation was due to increased BMP signaling in the cardiac cushions even though direct interaction between CXCR7 and BMP signaling is unclear. Endothelial cell-specific deletion of Cxcr7 using Tie2-Cre resulted in hypertrophy of the heart in adult mice because of semilunar valve stenosis, confirming important function of CXCR7 in endocardial-derived cells. This study provides valuable insight into the mechanism controlling cardiac cushion mesenchymal cell proliferation and may contribute to better diagnosis, treatment, and prevention of cardiac valve defects in humans.

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Receptors, CXCR, Heart Disease, Heart Valves

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