Preeclampsia (PE) is a hypertensive disease in pregnancy that is a leading cause of adverse maternal and fetal
outcomes in the US. Decades of clinical studies demonstrate that levels of the adipokine leptin inappropriately
increase, independent of body mass, in PE patients. However, whether leptin plays a role in the cardiovascular
and fetal outcomes of PE is unknown. We recently established a mouse model of leptin-induced PE, in which
exogenous leptin administration induces the clinical characteristics of PE in endothelial dysfunction,
hypertension, placental mitochondrial dysfunction and fetal growth restriction when given in mid-late gestation
pregnant mice. The goal of this proposal is to address a critical gap in knowledge regarding the stimuli
upregulating leptin in PE and to investigate mechanisms via which leptin induces adverse maternal and fetal
adaptations. Our central hypothesis is that sFlt-1 induces hyperleptinemia in PE, which promotes
hypertension and fetal growth restriction via endothelial dysfunction. Placental ischemia is a key initiating
event in PE and induces an anti-angiogenic milieu, most notably increasing soluble FMS like tyrosine kinase-1
(sFlt-1), the soluble form of vascular endothelial growth factor receptor 1 (VEGFR1). We show novel preliminary
data that sFlt-1 increases leptin production in both humans and mice. We also demonstrate that placental
ischemia, induced in the Reduced Uterine Perfusion Pressure (RUPP) mouse model of PE, increases circulating
leptin as well as sFlt-1. We will test in Aim 1 whether placental ischemia increases leptin levels via sFlt-1, which
mediates placental ischemia-induced endothelial and placental dysfunction. In this Aim, we propose that the
RUPP mouse develops endothelial dysfunction, hypertension, placental mitochondrial dysfunction and fetal
growth restriction, characteristics of PE, via leptin-mediated mechanisms. We will additionally investigate
whether sFlt-1 sequestration of VEGF reduces VEGF receptor signaling and promotes leptin production in PE.
Additional innovative preliminary data shows that endothelial leptin receptor activation increases the
production of endothelin converting enzyme-1 (ECE-1) and endothelin-1 (ET-1) in pregnant mice. We further
demonstrate that leptin upregulates endothelial mineralocorticoid receptor expression, which we have published
decreases ECE-1 expression. Therefore, in Aim 2 we will test whether leptin induces PE characteristics via
endothelial ET-1-mediated endothelial dysfunction. We will utilize mice with endothelial mineralocorticoid
receptor deletion as well as endothelial leptin receptor knockout mice to determine whether leptin-induced ET-1
expression by these endothelial pathways leads to PE characteristics in pregnant mice. We will further determine
whether ECE-1 induces vascular endothelial dysfunction and whether ECE-1 or ET-1 receptor antagonism
ablates leptin-induced PE. Collectively, the results of Aim 1 and 2 will significantly move forward the field
of leptin in PE and will give preclinical evidence if regulatory or downstream mechanisms of leptin in PE are
potential therapeutics to improve clinical care of PE patients.