Pregnancy is associated with substantial cardiovascular adaptations including dramatically increased maternal uterine blood flow (UBF) and fetoplacental blood flows for fetal nutrient delivery. Vasodilatation and angiogenesis are the mechanisms normally controlling maternal fetal perfusion, but perfusion is reduced in pregnancies complicated by intrauterine growth restriction (IUGR). Based on the Barker hypothesis, when reaching adulthood, these IUGR/small birth weight babies exhibit a host of adult onset diseases, including hypertension and its associated morbidity. It is of great importance to understand the causes and sequelae of IUGR. Limited uterine space in multi-fetal gestations and uterine anomalies cause IUGR from uterine and placental insufficiency. We developed a novel surgically-created ovine uterine space restriction model that partially maintained UBF with placental vasculature adaptations to sustain viable fetuses with asymmetric IUGR. We propose to utilize this model to study numerous physiological processes involved in placental, fetal, and postnatal vascular development. We will test the hypotheses that during uterine space restriction, both the maternal and fetal components of the placenta (uteroplacental/fetoplacental interface) and specifically their vasculatures initially adapt to preserve sustained fetal growth through partial maintenance of rises in uterine and fetal placental blood flows (Aim I) via NO-mediated vasodilatory (Aim II) as well as VEGF- and FGF2- mediated angiogenesis (Aim III) via cell and molecular signaling mechanisms. However, with growth arrest after 0.9 gestation, both vasodilatory and angiogenic mechanisms are inadequate, leading to placental insufficiency with consequent cessation of fetal growth velocity. Because the vascular adaptations ultimately define the postnatal cardiovascular phenotype of IUGR offspring, we will test the hypothesis that the outcome is postnatal programming of hypertension (Aim IV) with dysfunctional renal development, RAS activation, and altered blood volume and pressor studies in yearling lambs.
These aims will address vascular adaptation to decreased uterine space through physiological, signaling, and molecular mechanisms of vasodilatation and angiogenesis.
Programming of adult health and disease especially conditions of angiogenic growth restriction appear to be dependent upon fetal exposure to various in utero stresses. In this proposal we present a new model of uterine space restriction and its relationship to both uterine and placental vasculature adaptations as well as developmental programming of hypertension. Developmental programming and epidemiologic data in humans and agriculturally animal species have suggested that there is specific susceptibility to hypertension and this may also be altered by gender. This current proposal will yield important information that will aid in the development of pregnancy and postnatal strategies to prevent and treat hypertension through angiogenic factor mediated mechanisms.
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