Many changes occur in the maternal cardiovascular system with the onset of pregnancy and progress if pregnancy proceeds normally. The mechanisms responsible for these alterations are unclear. Similar uncertainties exist in our knowledge of the fetus and newborn. If pregnancy is to be successful, these changes must occur, in particular the dramatic increases in uteroplacental and fetoplacental blood flows necessary for fetal growth. It is likely that various steroid and peptide hormones and several vasoactive agents (e.g., EDRF, prostaglandins, etc.) are involved in these processes. The long term goal of this project is to determine how these factors are involved with vascular regulation, in particular those responsible for maintaining placental perfusion, and how they may differ in their actions on systemic vasculature.
The specific aims i nclude: delineating the ontogeny and mechanisms of regulation of angiotensin II (ANG II) vascular smooth muscle (VSM) receptors in the mother determining the ontogeny of changes in VSM function and growth in pregnancy (particularly uterine artery) defining mechanisms in VSM and endothelium that modify vascular reactivity in pregnancy; and determining the role of cyclic nucleotides in estrogen (E)-induce vasodilation and the role of E in vascular regulation. The pregnant ewe employed since similarities with the human are reported, and the uterine circulation can be studied in isolation. In intact animals uterine and systemic vascular responses to vasoactive agents are studied simultaneously, infusing agonist and/or antagonist locally via a uterine artery or systemically, while monitoring hemodynamic variables and blood levels of important vasoactive agents: PGI2, EDRF (cGMP), CAMP, ANG II, and E. Tissues are taken at completion of in vivo studies for evaluation of ANG II VSM receptor binding characteristics. VSM also is used to establish explants to study mechanisms responsible for arterial hypertrophy, shifts in myosin heavy chain isoforms, and alterations in stress generation and maximum shortening velocity. Other in vitro studies will examine the generation of cyclic nucleotides and determine if their source is VSM or endothelium; cell culture techniques will also be employed. MRNA for c-fos/c-myc oncogenes will be examined in VSM as markers of VSM hypertrophy or growth. If these specific aims can be addressed, mechanisms responsible for normal maternal adaptation will be better understood, thereby improving the approach to pathologic conditions seen in pregnancy, e.g., hypertensive disorders.
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