Glucocorticoid Programming of the Peripheral Vasculature

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Significance: We will evaluate normal ontogenic maturation and lifetime peripheral vascular effects of fetal glucocorticoid (GC) exposure. NIH recommends antenatal CG to accelerate fetal lung maturation. GC exposure increases peripheral vasoconstriction and fetal BP in sheep. Information on immediate and lifetime peripheral vascular effects of fetal GC exposure is limited. Our preliminary data in both fetus and adult demonstrate and altered peripheral vascular function after maternal GC administration. We propose specific hypotheses for endothelin (ET) receptors, ET receptor A and ET receptor B, nitric oxide (NO) and the physiological challenge of hypoxemia. We have two specific hypotheses for effects of maternal administration of dexamethasone (DM) on each of these end-points: 1) a single 48h DM course beginning 103 days gestation (dGA, 0.68 gestation -27 wks human gestation equivalent) alters fetal peripheral vascular responses; 3) a single 48h DM course beginning 103 dGA results in persistent altered peripheral vascular responses in adult life at three years of age. Approach: Chronically instrumented fetal sheep permit the most powerful combination of state-of-the-art techniques from whole animal to gene function to assess both fetal effects and lifetime programming in both a longitudinal time and tissue specific manner. We will conduct in vivo fetal and adult sheep studies beginning 103 dGA to determine mechanisms of prenatal GC programming on fetal and adult regional blood flows using microspheres and flow probes. Vascular reactivity will be studied in vitro using resistance vessel wire myography. We will evaluate the role of ET and NO in these altered peripheral vascular functions. We will study DM effects following a single 48h course. Animals will be studied in both fetal life and at 3 years of age. This multidisciplinary approach utilizes a unique infrastructural animal, physiological and biochemical laboratory environment with both in vivo, and in vitro physiological and molecular tools to study critical candidate systems at gene, cellular and whole animal levels. The investigator has worked with fetal sheep 38 years. The NYU investigators are an integrated group that has made the transition from Cornell together. We provide evidence that 1) prenatal DM exposure alters fetal vascular responses to ET and NO and gene function, 2) results in altered vascular responses at 3 years of age. In this resubmission we have tried to address the IRG concerns and strengthen the work by addition of RT-PCR identification of changes in critical genes (both those related to our hypotheses and other potential candidates) and improved our approach to potential differences according to fetal sex.