Novel mechanisms for leptin-mediated endothelial dysfunction in preeclampsia

Preeclampsia (PE) is a hypertensive pregnancy disorder afflicting up to 10% of pregnancies. PE patients develop new-onset hypertension in mid-late gestation along with a symptom of placental dysfunction. Clinical data demonstrates that PE patients increase placental midgestation leptin production, which is associated with PE severity. Our preliminary data characterizes a novel mouse model of PE, in which leptin is infused throughout mid-late gestation in pregnant mice. We show that leptin infusion induces FGR, endothelial dysfunction, hypertension and markers of placental dysfunction in pregnant mice. We also show that leptin infusion increases plasma endothelin-1 levels (ET-1) and endothelial-specific endothelin converting enzyme-1 (ECE-1) expression, which decreases with endothelial leptin receptor (EC-LepR) deletion. These data provided the rationale for our hypothesis that leptin increases endothelial ECE-1 and ET-1 production, which potentiates endothelial dysfunction, hypertension and FGR in mid-late gestation of pregnancy. We will test this hypothesis with two Specific Aims. In Aim 1, we will test the hypothesis that midgestation leptin infusion increases endothelial ET-1 production via endothelial leptin receptor-specific increases in ECE-1 activity. We will utilize transgenic mice, endothelial adenovirus techniques and pharmacological approaches to determine whether EC-LepR activation mediates leptin-induced reductions in NO bioavailability, endothelial dysfunction, hypertension and FGR in pregnancy dependent on endothelial ECE-1 activity. In Aim 2, we will test the hypothesis that leptin-induced endothelial dysfunction reduces placental blood flow and promotes FGR and hypertension. We will measure functional measures of placental blood flow, uterine artery resistance, endothelial function and blood pressure to determine whether leptin infusion reduces fetoplacental perfusion dependent on EC-LepR and ECE-1 activity. In collaboration with a mentoring team of experts in vascular signaling, function and pregnancy mechanisms, the results of this proposal will advance the PE field by providing 1. Evidence of the role of EC-LepR activation and ECE-1 activity in PE pathogenesis and 2. A novel PE mouse model with numerous future directions of study. In addition, this CDA will facilitate the applicant's transition to independent faculty providing graduate/postdoctoral projects, manuscripts and will lay the groundwork for future extramural funding.