DIFFERENTIATION, DEDIFFERENTIATION, AND APOPTOSIS OF SMOOTH-MUSCLE CELLS DURING THE DEVELOPMENT OF THE HUMAN DUCTUS-ARTERIOSUS

Differentiation of vascular smooth muscle cells (SMCs) is characterize d by several molecular transitions. As differentiation proceeds, prote ins of the cytoskeletal and contractile apparatus, such as alpha-smoot h muscle actin, smooth muscle myosin, calponin, and heavy caldesmon, a nd the expression of the membrane-related protein smooth muscle phosph oglucomutase-related protein increase, whereas the expression of other proteins, such as fibronectin splice variants with extradomains A (ED A) and B (EDB), decreases. In this study, we investigated the differen tiation of the SMCs of the ductus arteriosus during the development of intimal thickening. Ascending and descending aortas of the same age w ere used for comparison because these vessels lack intimal thickening. In the fetal ductus arteriosus, a relatively early differentiation of the contractile apparatus was observed compared with the ascending an d descending aortas. EDA and EDB expression was already low, being sim ilar in the ductus and descending aorta and even lower in the ascendin g aorta. In the neonatal ductus, SMCs of the media and outer intima we re well differentiated and comparable with SMCs of the ascending aorta . Dedifferentiated SMCs, with a low expression of cytoskeletal and con tractile proteins and a high expression of EDA and EDB, were found in regions in the inner intima that show features of progression of intim al thickening and in areas of cytolytic necrosis in the media. With a technique using in situ end labeling of DNA fragments, we found extens ive apoptosis in the area of cytolytic necrosis and to a lesser extent in these areas of the inner intima. In conclusion, SMCs of the fetal ductus arteriosus have an advanced differentiation of the contractile apparatus compared with the adjacent aorta. Reexpression of fetal char acteristics is seen in a number of cells in inner intima and media of the neonatal ductus arteriosus. The finding of apoptosis in these area s suggests that dedifferentiation and apoptosis are associated process es that may play a role in vascular remodeling.