The main objective of this proposal is to develop strategies to enhance endothelial maturation and regulation of vasomotor tone so as to ensure better vascular function in the prematurely delivered newborn. Knowledge regarding the role of vascular endothelium in regulation of tone in the underlying smooth muscle has increased considerably in recent years, however, little is known about the developmental aspects of endothelial regulation of vasomotor tone in the perinatal period. Data from preliminary studies in the ovine species indicate that endothelial derived factors play a very important role in regulation of vasomotor tone during the perinatal period. Also, other preliminary data indicate that antenatal glucocorticoid administration to the immature ovine fetus improves the postnatal adaptive changes in the vascular system.
The specific aims of this proposal are designed to test the hypotheses that in the developing fetus: a) antenatal drug (glucocorticoid, thyroxine, epidermal growth factor) therapy to the immature fetus accelerates endothelial maturation globally and facilitates postnatal adaptation of the vascular system in the prematurely delivered newborn; b) the role of endothelial derived factors, specifically that of nitric oxide, endothelin, platelet activating factor and eicosanoids, in regulation of vascular smooth muscle tone undergoes distinct maturational changes; c) the balance of action of endothelium derived factors is such that resistance in the systemic circulation increases with development in utero and postnatally whereas that in the pulmonary circulation is high in utero and falls after birth. In vitro studies will be done in isolated segments of systemic and pulmonary arteries and veins as well as in vivo studies in the immature and mature ovine fetus, after delivery. To investigate the role of endothelial derived factors in regulation of vasomotor tone, specific receptor blockers and inhibitors of synthetic enzymes will be utilized. The effect of antenatal drug therapy on a) the integrity and stability of the vascular system and on endothelial function in the immature fetus, b) on the maturational changes in endogenous production of endothelial factors by different vessel types, and c) on the developmental changes in physiological responses of different vessel types and vessel sizes, will be studied. Prematurely delivered infants suffer from significant mortality and morbidity resulting from dysfunction of multiple organ systems including the vascular system. Knowledge derived from these studies should enable us to determine optimum antenatal drug therapy so as to improve vascular function in the prematurely delivered infant and thereby reduce overall neonatal mortality and morbidity.
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