Three inter-related RO- 1 grants are proposed to elucidate the pathogenesis of preeclampsia, an obstetrical disease affecting as many as 10% of women in their first pregnancy. This disease, characterized by hypertension, edema, and proteinuria, is frequently complicated by thrombocytopenia, liver and kidney lesions and in its severest form, widespread intravascular coagulopathy, seizures and death. The three projects will test the hypothesis that dysregulation of the urokinase plasminogen activator system and the alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein system account for the deficient invasion of trophoblast cells into the endometrium and failure of the remodeling of the uterine spiral arteries, which are histopathologic hallmarks of preeclampsia. The second hypothesis is that placental hypoxemia, a consequence of the retention of smooth muscle around uterine arteries and release of vasoconstrictor substances affects placental function and leads to release of additional vasoactive substances that increase blood pressure and activate platelets. The three projects bundled in response to this RFA are complimentary in their specific aims and utilize related methodologies. They will examine the regulation and role of the urokinase and alpha2-macroglobulin receptor systems in normal and preeclamptic pregnancies using biochemical and immunohistochemical techniques. The functional activities of these proteins will be examined utilizing model in vitro of trophoblast invasion. The collaborative approach will provide opportunities for synergistic interactions that will speed the completion of research goals and lead to new understanding of the pathophysiology of a disease that causes significant morbidity and mortality in young women.
