Depressed uterine artery contractility plays a key role in the striking increase of uterine blood flow during pregnancy which ensures normal fetal development. Yet the mechanisms underlying the vascular adjustments to pregnancy are not understood. Further, the normal adaptation of uterine artery contractility to pregnancy can be interfered with hypoxia resulting in an increased vascular resistance and a reduction in uterine blood flow. The general aim of the proposed studies is to explore the mechanisms by which uterine artery contractile mechanisms adapt to pregnancy, and how this adaptation is altered by hypoxia. We hypothesize that decreased uterine artery contractility during pregnancy is due to the adjustments of both endothelial and vascular smooth muscle functions, whereas hypoxia interferes with one or more of these normal adaptations, and results in an increase of the vascular resistance. The research plan is designed to test several specific hypotheses using isolated sheep uterine arteries. We will test the hypothesis that pregnancy increases uterine artery endothelial nitric oxide synthesis/release, and acute hypoxia inhibits this increased endothelial function. We will then test the hypothesis that pregnancy decreases uterine artery smooth muscle alpha1-adrenergic and serotonin2 receptor densities and agonist binding affinities, and acute hypoxia increases agonist binding affinities. We will also test the hypothesis that pregnancy attenuates inositol 1,4,5-trisphosphate (IP3) synthesis and depresses intracellular Ca2+ release in uterine artery smooth muscle, and acute hypoxia enhances IP3 synthesis and elevates intracellular free Ca2+ concentration. Further, we will test the hypothesis that the importance and mechanisms of the vascular adjustments to pregnancy and their alterations by acute hypoxia vary as a function of artery generation. The results of these studies will reveal the mechanisms underlying increased uterine blood flow during pregnancy. Not only is this of basic physiological importance, elucidation of these mechanisms will also lead to greater insights into pathophysioIogy of clinical problems associated with the dysregulation of uterine blood flow. Indeed, the outcomes of proposed studies will provide original new information related to the mechanisms by which acute hypoxia contracts the uterine artery in pregnant animals. In so doing, they will provide a basis for and facilitate future studies related to the effects of long-term hypoxia on uterine artery contractility, which is of great interest in human pregnancy exposed to chronic hypoxia.
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