In the full-term neonate, the ductus arteriosus constricts rapidly after delivery in order to separate the pulmonary from the systemic circulations. Failure of the ductus to close after birth results in significant morbidity: chronic lung disease, necrotizing enterocolitis, etc. Permanent closure of the ductus arteriosus is accomplished by extensive remodeling of the vessel wall: SMCs from the muscle media migrate into the intima to form intimal mounds that occlude the lumen. This process frequently does not take place in the premature human infant. The general hypothesis to be tested in this proposal is that initial ductus arteriosus constriction induces the remodeling process and that during ductus remodeling, smooth muscle cells (SMCs) in the outer muscle media differ from those in the inner media in their ability to respond to newly synthesized growth factors and in the mechanisms that initiate growth factor synthesis.
The specific aims of this project are: 1) to examine the factors that initiate growth factor (e.g., the TGF/Beta's, endothelin-1, and VEGF) synthesis in different parts of the vessel wall: the degree of SMC mechanical tension, changes in oxygen tension, susceptibility or resistance to ischemia; 2) to examine the tractional and migratory effects of growth factors on SMCs and the signals mediating these effects; 3) to examine whether the factors responsible for ductus constriction change during the first days after delivery. These studies will be accomplished by using animal models that prevent the ductus arteriosus from closing after birth, and models that close the ductus prior to birth, both early and late in gestation. They will also use cell culture and organ culture models to study the processes of SMC migration, contraction, oxygen consumption, extracellular matrix remodeling, and growth factor production. They will utilize measurements of hemodynamic variables, isolated vessel tension, cell migration, cell-matrix contraction, immunochemistry, immunohistochemistry, in situ hybridization, and Northern analysis. These studies should increase our understanding of what initiates and sustains the process of ductus remodeling after birth and why it does not occur in the preterm infant.
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