Collagen XVIII/endostatin is associated with the epithelial–mesenchymal transformation in the atrioventricular valves during cardiac development

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Abstract
Type XVIII collagen is a multidomain protein that contains cleavable C‐terminal NC1 and endostatin fragments, which have been shown to either induce or inhibit cell migration. Endostatin is being intensely studied because of its anti‐angiogenic activity. Three variants of type XVIII collagen have been reported to be distributed in epithelial and endothelial basement membranes in a tissue‐specific manner. The single gene encoding collagen XVIII is on chromosome 21 within the region associated with the congenital heart disease phenotype observed in Down's syndrome. In this study, we investigated the expression pattern of collagen XVIII in embryonic mouse hearts during formation of the atrioventricular (AV) valves. We found that collagen XVIII is localized not only in various basement membranes but is also highly expressed throughout the connective tissue core of the endocardial cushions and forming AV valve leaflets. It was closely associated with the epithelial–mesenchymal transformation of endothelial cells into mesenchymal cushion tissue cells and was localized around these cells as they migrated into the cardiac jelly to form the initial connective tissue elements of the valve leaflets. However, after embryonic day 17.5 collagen XVIII expression decreased rapidly in the connective tissue and thereafter remained detectable only in the basement membranes of the endothelial layer covering the leaflets. The staining pattern observed within the AV endocardial cushions suggests that collagen XVIII may have a role in cardiac valve morphogenesis. These results may help us to better understand normal heart development and the aberrant mechanisms that cause cardiac malformations in Down's syndrome. Developmental Dynamics 235:132–142, 2006.

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