Download the chemokine receptor cxcr7 functions in endocardial

THE CHEMOKINE RECEPTOR CXCR7 FUNCTIONS IN
ENDOCARDIAL-DERIVED CELLS TO REGULATE CARDIAC VALVE
REMODELING
Sangho Yu, Ph.D.
The University of Texas Southwestern Medical Center at Dallas, 2009
Supervising Professor: Deepak Srivastava, M.D.
Full PDF available after 12/1/2012
Keywords: CXCR7; RDC1; heart development; chemokine receptor; similunar valves; stenosis;
endocardial cushion
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 cellspecific 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 endocardialderived 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.