TY - JOUR
T1 - Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction hypertension, and proteinuria in preeclampsia
AU - Maynard, Sharon E.
AU - Min, Jiang Yong
AU - Merchan, Jaime
AU - Lim, Kee Hak
AU - Li, Jianyi
AU - Mondal, Susanta
AU - Libermann, Towia A.
AU - Morgan, James P.
AU - Sellke, Frank W.
AU - Stillman, Isaac E.
AU - Epstein, Franklin H.
AU - Sukhatme, Vikas P.
AU - Karumanchi, S. Ananth
PY - 2003/3
Y1 - 2003/3
N2 - Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (P1GF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and P1GF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and P1GF. Additionally, VEGF and P1GF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
AB - Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (P1GF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and P1GF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and P1GF. Additionally, VEGF and P1GF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
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U2 - 10.1172/JCI17189
DO - 10.1172/JCI17189
M3 - Article
C2 - 12618519
AN - SCOPUS:0037373006
VL - 111
SP - 649
EP - 658
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
ER -