Plasminogen activator inhibitor 1 (PAI1) as a therapeutic target for maternal endothelial dysfunction in preeclampsia

Summary Preeclampsia is a hypertensive disorder of pregnancy that causes 70,000 maternal and 500,000 neonatal deaths per year globally. The only specific treatment is delivery of the baby and placenta, resulting in 3-4 times more frequent preterm birth compared to normotensive pregnancies. The underlying pathophysiology of preeclampsia is likely heterogeneous, but the culmination is maternal endothelial dysfunction causing hypertension, kidney failure, coagulopathy, and strokes. A history of preeclampsia is associated with ischemic heart disease and renal failure for the mother and long-term cardiovascular disease in the offspring. Therapies that specifically improve maternal endothelial function are urgently needed to permit safe pregnancy prolongation and improve mother and child outcomes. Plasminogen activator inhibitor 1 (PAI1) is elevated in preeclampsia, yet its pathophysiologic role is unknown. PAI1 plays a deleterious role in numerous cardiovascular diseases, and pharmaceuticals are in development. We and others have shown that PAI1 promotes endothelial dysfunction through inhibition of endothelial nitric oxide synthase and promotion of inflammatory and vasoactive genes that are upregulated in preeclampsia. PAI1’s role in hemostasis is important in pregnancy, but our preliminary findings suggest that PAI1-mediated inflammation is independent of its role in the coagulation cascade. These data suggest PAI1 contributes to the pathophysiology of preeclampsia and make it a promising therapeutic target. The objective of this proposal is to gain insights into maternal endothelial dysfunction that can be leveraged to develop novel therapeutic strategies with a specific focus on PAI1 as a drug target. In Aim 1, we test whether PAI1’s inflammatory effect can be blocked without disrupting its role in hemostasis by identifying how PAI1 alters inflammatory signaling pathways and determining the molecular interactions required. In Aim 2, we test the relevance of PAI1-mediated endothelial dysfunction in plasma from patients with preeclampsia using a PAI1 inhibitor. We use statistical models to associate clinical and biochemical characteristics with the effect of preeclamptic plasma on endothelial function. In Aim 3, we use a mouse model that recapitulates endothelial dysfunction in preeclampsia to test the role of PAI1 in mediating systemic effects including blood pressure, vascular function, cytokines, and renal damage. We test the in vivo efficacy of blocking PAI1 therapeutically. There is no treatment for preeclampsia, which leads to long-term cardiovascular disease for mother and child. This project mechanistically investigates the therapeutic potential of targeting PAI1 to improve endothelial function while also collecting new hypothesis-generating data about the effect of plasma proteins in preeclampsia on the endothelium. Our studies will drive future drug discovery to specifically target endothelial function with the goal of prolonging pregnancy and improving the health of the mother and baby. Project Number: 1R01HL181577-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Molly McAdow | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $806,978 | Activity Code: R01 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18157701