IGF AXIS IN PULMONARY VASCULAR REMODELING

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The role of IGF-II and IGF-BP's in the dramatic pulmonary vascular remodeling associated with neonatal pulmonary hypertension will be studied. The fibroproliferative response in this disease characterizes the neonate, and may represent a unique developmental susceptibility to injury at a time of marked changes in circulatory physiology and vessel maturation. Our preliminary data suggest a role for increased expression of IGF-II in the vascular proliferative response. IGF-BPs produced by vascular wall cells play a central role in localizing and modulating IGF actions at the cellular level. We hypothesize that increased IGF-II expression in the pulmonary vessel wall is a critical modulator of the vascular proliferative response in neonatal hypoxic pulmonary hypertension. We propose that increased IGF-II expression in neonatal pulmonary hypertension reflects persistence of a fetal pattern of gene expression in the perinatal period, associated with altered expression and accumulation of specific IGF-BP's. We postulate that altered expression of IGF-II and IGF-BP's is regulated by hypoxia in vitro, with different effects on the adventitial fibroblast and vascular smooth cell. The goals are: 1) to evaluate the normal developmental changes in IGF-II and IGF-BP expression in the pulmonary circulation during late fetal and early neonatal life, and how these are affected by developing hypoxic pulmonary hypertension in the newborn, and 2) to examine directly how hypoxia alters expression of IGF-II and IGF-BPs in fetal, neonatal, and hypertensive vascular wall cells in vitro.