DUCTUS ARTERIOSUS ENDOTHELIAL CELLS AND SMOOTH MUSCLE CELLS ALTER THEIR INTEGRIN EXPRESSION TO PRODUCE PERMANENT POSTNATAL CLOSURE. • 1198

Abstract

Following muscular constriction of the ductus arteriosus in the first hours after delivery, extensive neointimal thickening is required to produce permanent occlusion of the ductus lumen. In premature infants, despite, smooth muscle constriction, neointimal mounds frequently fail to develop, resulting in vessel reopening. Neointimal mounds are formed by luminal endothelial cells(ECs) and medial smooth muscle cells (SMCs) that migrate into the subendothelial space. The migration of ECs and SMCs requires the presence of cell surface receptors (integrins) that interact with the surrounding extracellular matrix (ECM). The ability of the integrin receptors to bind to different ECM molecules is determined by the combination of α and β subunits that make up the integrin receptor. Using immunohistochemical techniques, we examined ductus arteriosus obtained from 4 fetal and 11 four-day-old newborn (3 full-term and 8 preterm [78% gestation]) rhesus monkeys to determine the effects of gestational age on postnatal integrin expression and ductus remodeling. In the fetal ductus, ECs lining the vessel's lumen have a limited repertoire of integrins (weak expression ofα1β1 and minimal to negligible expression of otherβ1, β3, β4, β5, andβ6 integrins). In contrast, ECs of capillaries invading the ductus adventitial layer strongly express several integrins(α1β1, α2β1,α3β1, α6β1,αVβ5, α6β4). During postnatal closure, luminal ECs of the full-term ductus change their phenotype and express the identical repertoire of integrins found on migrating capillary endothelial cells. Similarly, after birth, SMCs in the closing ductus change their phenotype and express 2 additional integrins(α5β1 and αVβ3) that we have previously shown to be necessary for SMC migration in vitro. Among the 8 preterm ductus, 3 had lumens that were occluded by neointimal formation; the integrin profiles of the ECs and SMCs of these 3 ductus were identical to those expressed by cells of the full-term postnatal closed ductus. In contrast, 5 preterm newborns with persistently patent ductus lumen failed to develop these postnatal changes in integrin expression and failed to develop neointimal mounds. No evidence of intimal thickening occurred in the absence of changes in integrin expression. These findings show that during ductus closure, ECs and SMCs change their phenotype and express integrins found on migrating cells; this enables them to produce the neointimal mounds necessary for permanent closure.