The pathophysiology of pregnancy-induced hypertension (PIH) is unknown, but appears to involve an intrinsic defect in trophoblast cell migration. The factors that regulate this migration have not been elucidated, but one such factor may be the oxygen tension which cytotrophoblast cells encounter once implantation has occurred. Cytotrophoblast cell migrate under the low oxygen tension present in decidual tissue and migration essentially ceases once a maternal arterial-placental blood supply has been established-Oxygen tension may thereby regulate cytotrophoblast cell proliferation, differentiation and the formation of proteases such as plasmin that are involved in migration and vascular remodeling. In PIH, the failure of cytotrophoblast cells to elaborate plasmin under hypoxic conditions may part of the fundamental defect in cell migration. Because the migration of cytotrophoblasts into the maternal vessels is impaired in PIH, the remodeling of maternal uterine arteries that occurs during the first trimester in uncomplicated pregnancy is incomplete. Smooth muscle cells persist in the distal portions of these vessels at term where they are found in apposition to trophoblast cells. Trophoblast cells produce thromboxanes and prostacylin and we have observed recently that they secrete big-endothelin-1 and express endothelin converting enzyme as well. Production of endothelin and thromboxanes by trophoblast cells may be stimulated by hypoxia which, in turn, may cause the incompletely remodeled uterine arteries in PIH to undergo vasoconstriction, further impairing placental blood flow. To date, essentially all studies of cultured human trophoblast cells have been performed under oxygen tensions (21% 02, 150 mmHg) well above those encountered by migrating cytotrophoblast cells in vivo (7% 02, 40-50 mmHg). Therefore, we will examine the effect of physiologic oxygen tension and hypoxia on several functions of cytotrophoblast cells that may be involved in the pathogenesis of PIH and its clinical manifestations. Specifically, we will determine whether oxygen tension: 1. regulates cytotrophoblast cell proliferation, differentiation and the production of betaHCG and prolactin; 2. coordinately regulates cytotrophoblast production of urokinase, urokinase receptors, urokinase inhibitors and the alpha2-macroglobulin receptor clearance pathway so as to enhance the production of plasmin; 3. stimulates the production of endothelin and thromboxanes at the expense of prostacyclin. The behavior of cytotrophoblast cells from patients with PIH will be compared with normal and hypoxic cells. These studies will help to elucidate the role of placental ischemia in the pathogenesis and clinical manifestations of PIH.
