Preeclampsia (PE) is a disease, which affects 5-7% of all pregnancies and is characterized by severe hypertension, proteinuria and edema. Endothelial dysfunction plays an important role in the pathogenesis of this disorder; however, the etiology and mechanisms are still unknown. We recently found that placentas from preeclamptic patients produce an excess of a naturally occurring anti-angiogenic protein, sFIt-1 (soluble fms-like tyrosine kinase-1), resulting in increased serum levels in patients with PE as compared to normotensive pregnant women. Fit-1 is one of the tyrosine kinase receptors for vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). sFIt-1, a secreted splice variant of Fit-1 (lacking the transmembrane and cytoplasmic domains) potently antagonizes VEGF and PIGF, by preventing their binding to the cell-surface receptor. Moreover, we have found that the ratio of anti-angiogenic (sFIt-1) to pro-angiogenic (VEGF + PIGF) proteins in the maternal bloodstream at the time of delivery is substantially elevated in preeclamptic women as compared with control pregnant women. In vitro, preeclamptic serum but not normal pregnant serum induces endothelial dysfunction due to excess sFIt-1, which can be rescued by exogenous VEGF and PIGF. Finally, we have preliminary data that administration of exogenous sFIt-1 to pregnant rats induces hypertension, heavy proteinuria and glomerular endotheliosis, the classic lesion of PE. We therefore hypothesize that alteration in the angiogenic balance due to excess sFLt-1 results in the development of PE. This proposal aims to clarify the role of sFIt-1 and altered angiogenic balance in the pathogenesis of PE. We will first characterize our sFIt-1 induced animal model for PE and will test several therapeutic compounds in an attempt to find new treatment options for patients with PE. We will then elucidate the mechanisms of systemic vascular dysfunction and placental cytotrophoblast dysfunction induced by excess sFIt-1 and altered angiogenic balance using both in vitro and in vivo experiments. Finally, we will focus on studying the transcriptional and post-transcriptional regulatory mechanisms of sFIt-1 production by placental cytotrophoblasts. These focused studies will form the beginnings of a framework for understanding the role of angiogenesis-related gene products in pathogenesis of PE and for exploring novel avenues for the treatment of PE.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079594-03
Application #
7174642
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Barouch, Winifred
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$322,381
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Holston, Alexander M; Qian, Cong; Yu, Kai F et al. (2009) Circulating angiogenic factors in gestational proteinuria without hypertension. Am J Obstet Gynecol 200:392.e1-10
Maharaj, Arindel S R; Walshe, Tony E; Saint-Geniez, Magali et al. (2008) VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med 205:491-501
Bdolah, Yuval; Lam, Chun; Rajakumar, Augustine et al. (2008) Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 198:428.e1-6
Maynard, Sharon; Epstein, Franklin H; Karumanchi, S Ananth (2008) Preeclampsia and angiogenic imbalance. Annu Rev Med 59:61-78
Signore, Caroline; Mills, James L; Qian, Cong et al. (2008) Circulating soluble endoglin and placental abruption. Prenat Diagn 28:852-8
Mutter, Walter P; Karumanchi, S Ananth (2008) Molecular mechanisms of preeclampsia. Microvasc Res 75:1-8
Karumanchi, S Ananth; Lindheimer, Marshall D (2008) Preeclampsia pathogenesis: ""triple a rating""-autoantibodies and antiangiogenic factors. Hypertension 51:991-2
Kopcow, Hernan D; Karumanchi, S Ananth (2007) Angiogenic factors and natural killer (NK) cells in the pathogenesis of preeclampsia. J Reprod Immunol 76:23-9
Karumanchi, S Ananth; Lindheimer, Marshall D (2007) Preeclampsia and the kidney: footprints in the urine. Am J Obstet Gynecol 196:287-8

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