Mechanisms of Dyslipidemia following Preeclampsia

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Abstract

ABSTRACT Preeclampsia, a multi-systemic disorder of pregnancy that typically presents with new onset proteinuria and hypertension, is associated with significant morbidity to mother and fetus. Mothers with a history of preeclampsia have also increased risk of long-term cardiovascular and end-stage renal disease. Epidemiological studies have suggested that human gestation is characterized by atherogenic lipid profile that is further enhanced in preeclampsia. In this proposal, we posit that increased circulating levels of soluble fms- like tyrosine kinase 1 protein (sFlt1), an endogenous anti-angiogenic protein that is linked with the pathogenesis of preeclampsia, directly induces dyslipidemia by inhibiting vascular endothelial growth factor (VEGF) signaling in the hepatic sinusoidal endothelium. Liver sinusoidal endothelium express fenestrae (`open pores') that allow for regulation of lipoprotein metabolism and the occurrence of atherosclerosis. In aim 1, we will test the hypothesis that excess circulating sFlt1 inhibits VEGF signaling across hepatic vasculature leading to loss of endothelial fenestrae. We expect that defenestration will lead to excess atherogenic lipoproteins in the plasma and that the dyslipidemia will correlate with vascular lesions such as ?atherosis? that are characteristic of severe preeclampsia. We will then evaluate whether the rescue of preeclampsia phenotype using recombinant VEGF protein will lead to a reversal of the vascular endothelial damage and the accompanying dyslipidemia. In aim 2, we will measure lipid profile during the third trimester in a cohort of patients in whom we have access to detailed clinical phenotypes (preeclampsia, gestational hypertension) and circulating angiogenic protein levels. We expect that preeclampsia will be characterized by atherogenic lipid profile that will correlate with circulating levels of sFlt1. We have generated preliminary data that supports both aims. In summary, the proposed studies will test an innovative hypothesis that endothelial disease induced by anti-angiogenic factors lead to dyslipidemia which in turn contributes to the pathogenesis of both short term and long term complications of preeclampsia.