Maternal Androgen Excess: Vascular and Placental Function and Fetal Consequences

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DESCRIPTION (provided by applicant): Elevated maternal androgen levels during pregnancy programs development of increased blood pressure and vascular, reproductive, and endocrine dysfunction in offspring in adult life. Whether this programming effect is exerted directly on the embryo and fetus, or indirectly via effects on the mother, is unknown. Based on our preliminary data that testosterone does not cross placenta and the observation of vascular and placental defects in pregnant rats with elevated T, we hypothesize that elevated maternal T impairs cardiovascular (CV) adaptations and placental function to compromise the development of the fetus, thereby leading to the development of adult diseases. Thus, the focus of this proposal is to investigate the mechanisms of androgen- induced maternal CV and placental dysfunctions. Two specific aims are proposed. Specific Aim 1: Characterize the influence of elevated T on maternal CV function. Question 1a: Does elevated T alter blood pressure (BP) in the mothers? We hypothesize that elevated T will increase mean arterial pressure in dams. Question 1b: Does elevated T alter vascular endothelial function in mothers? We hypothesize that nitric oxide (NO) production, eNOS expression, and endothelium-dependent vasodilator function in arteries of mesenteric and uterine vasculature is affected in mothers with elevated T. Question 1c: Is vascular smooth muscle (VSM) cell function altered in T dams? We hypothesize that VSM contractile response is increased in mesenteric and uterine vasculature of T dams. Specific Aim 2: Investigate the influence of elevated T on placental function. Question 2a: Does elevated maternal T cause placental dysfunction? We hypothesize that in T-treated mothers, the placental weight, especially labyrinth zone, size will be reduced with decreases in proangiogenic and increases in antiangiogenic factors. Question 2b: Does elevated maternal T alter placental nutrient transport capacity? We hypothesize that T will decrease the expression and activity of transporters, leading to decreased transfer of amino acids and glucose across the placenta to the fetus. These studies are of significance, especially in the view of higher androgen levels reported in several obstetric pathological conditions that may lead to intrauterine growth restriction, such as preeclampsia, maternal PCOS, obesity, stress, and smoking. In addition, pregnant African-American mothers have higher serum T levels and a greater frequency of low-birth-weight babies. Moreover, the highest rates of maternal and adult CV dysfunction are also concentrated in these populations. Our rat model presents an opportunity to investigate the adverse effects of elevated maternal androgens, which may aid in improving maternal and fetal health. PUBLIC HEALTH RELEVANCE: Programming of adult health and disease appears to be dependent upon fetal exposure to various in utero environmental factors. Pilot data from our group have highlighted that exposure in utero to elevated androgens causes low birth weight and adult hypertension and further suggest that cardiovascular dysfunction and placental insufficiency may underlie these effects. This proposal will yield important insights that could aid in the development of effective diagnostic tools and interventions to prevent or decrease maternal cardiovascular risk and associated effects on low birth weight and adverse health consequences in adult life.