DESCRIPTION (Verbatim from the application): Venoarterial transfer offers a pathway through which vasoactive and growth-promoting factors in the placental effluent can potentially influence the behavior and structure of adjacent uterine arteries. This project is designed to explore this concept, and is structured around four Specific Aims that will establish the biophysical (AIM 1) and physiological (AIM 2) properties of venoarterial transfer, determine how this process is altered during pregnancy (AIM 3), and evaluate the role of three specific molecular signals (estrogen, progesterone, VEGF) in its regulation. Experiments will be carried out using a novel in vitro system in which paired, adjacent segments of uterine arteries and veins are cannulated and studied using fluorescent tracer molecules (to determine permeability) and by directly observing the effects of intravenous vasoactive compounds on arterial diameter under conditions in which the physical and chemical environment is finely controlled (signal transfer). Working hypotheses are presented under each aim and include the following: AIM 1: (1) Vasoactive substances within the venous lumen are capable of exerting a significant, bi-directional (contraction, dilation) modulatory effect on the lumen diameter of an adjacent uterine artery. (2) The bioavailability of a particular compound is primarily dependent on its concentration, molecular weight and venous transmural pressure. (3) The effects of transmural pressure are proportional and related to circumferential wall tension. AIM 2: (4) Calcium and the phospholipase C-protein kinase C system are important modulators of venous permeability through their actions on endothelial actin:myosin interactions. AIM 3: (5) Pregnancy alters the structure and functional properties of the venous endothelium in a way that augments venoarterial transfer of vasoactive and mitogenic stimuli. AIM 4: (6) Estrogen, progesterone and VEGF are important molecular determinants of venoarterial transfer. (7) The permeability-enhancing effects of VEGF are partly effected through its stimulation of nitric oxide secretion from the venous endothelium. Preliminary data to support each hypothesis are provided in the text of this application. These studies will provide new, quantitative information on the mechanisms by which molecular signals and pregnancy modulate venous permeability and signal transfer within the uterine circulation.