PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) is a common and life-threatening hypertensive disorder of pregnancy. This disease affects nearly 7% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality. There are currently no therapies that treat PE except for early delivery. Data from our lab and others suggest that women with PE have angiogenic imbalance (excess soluble fms-like tyrosine kinase 1 [sFlt1]), evidence of inflammation (excess tumor necrosis factors TNF-?, interleukins such as IFN-?-inducible protein 10-IP-10 and IL-6) and excess reactive oxygen species (ROS). The release of these soluble factors from the placenta into the bloodstream interferes with the supply of pro-angiogenic factors, such as placental growth factor (PlGF), resulting in reduced nitric oxide (NO) and increased endothelin-1 (ET-1), and ultimately endothelial dysfunction and hypertension. The lack of treatment options for PE likely results from its complex etiology and limitations on drug use during pregnancy. Identifying a safe therapeutic for this condition is a major unmet need for the health of pregnant women. The availability of chemical libraries and high-throughput screening methodologies has allowed investigators to discover novel molecules that interfere with signaling pathways involved in disease biology. We screened a chemical library of natural compounds and identified the bioflavonoid, luteolin, as a potent inhibitor of sFlt1 in human placental cell lines and placental explants. In addition, we discovered that luteolin inhibits a variety of pro-inflammatory cytokines (such as IL-1, IL-27, IL-6 and IP-10) and interrupts distinct cellular pathways that inhibit several key proteins implicated in pathogenesis of PE. Specifically, we found the luteolin is a potent inhibitor of hypoxia-inducible factor 1? (HIF-1?, a major regulator of sFlt1). In addition, luteolin reduces TNF- ? induced ET-1 production in vitro, reduces blood pressure, relaxes uterine arteries, improves placental perfusion in placental ischemia rat models of PE. Our exciting and novel preliminary data led us to propose the central hypothesis that luteolin improves uterine perfusion and reduces total peripheral resistance and blood pressure in models of PE by reducing placental production of sFlt1 and HIF-1? and inhibiting cytokines such as IP-10 and TNF ?. In addition, we propose that luteolin decreases blood pressure by inhibiting TNF-? and sFlt1-induced endothelial production of ET-1. To test this hypothesis, we will use human placental explants, cytotrophoblast cell lines, cultured endothelial cells, isolated blood vessels, as well as molecular, pharmacological and physiological techniques in novel animal models of PE, the Reduction in Uterine Perfusion Pressure (RUPP) model and the sFlt1 model. Our specific aims and central hypothesis are backed by strong preliminary and feasibility data. The proposed experiments will identify mechanisms by which luteolin interferes with the pathophysiological pathways linking placental ischemia with maternal cardiovascular dysfunction, while generating preclinical data to support the development of luteolin as a therapy for PE.

R56HL157579

2021-09-20

2022-08-31