Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia.
OBJECTIVE
Soluble fms-like tyrosine kinase (sFlt-1) is an important mediator in the pathogenesis of preeclampsia. We sought to determine whether platelet-monocyte aggregates (PMAs) produced sFlt-1 and whether PMAs contributed to sFlt-1 production in preeclampsia.


METHODS
This was a case-control study of sFlt-1 release from PMAs using blood samples from women with preeclampsia matched by gestational age to pregnant controls. A third group of nonpregnant, reproductive-age women comprised an additional control group. Experiments were also performed using blood from nonpregnant women to elucidate whether inducing PMAs could stimulate sFlt-1 production and, if so, to determine the necessary receptors and pathways.


RESULTS
Women with preeclampsia had increased total Flt-1 concentrations in platelets and monocytes at baseline compared with pregnant controls (25 vs 10 pg/mL, P = .0003). sFlt-1 production was elicited from monocytes incubated with thrombin-activated platelets from nonpregnant women. sFlt-1 production was regulated at the transcriptional level by p38 and nuclear factor-κB-dependent pathways.


CONCLUSIONS
Activated platelets in preeclampsia bind monocytes to generate sFlt-1. PMAs are a previously unrecognized source of sFlt-1 that may contribute to endothelial dysfunction and systemic inflammation commonly observed in preeclampsia.
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Molecular Medicine Program, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT.
Heather D
HD
Major
Department of Internal Medicine, Eccles Institute of Human Genetics, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT.
Robert A
RA
Campbell
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Molecular Medicine Program, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT.
Robert M
RM
Silver
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Molecular Medicine Program, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT.
D Ware
DW
Branch
Department of Internal Medicine, Eccles Institute of Human Genetics, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT. Electronic address: andy.weyrich@u2m2.utah.edu.
Andrew S
AS
Weyrich
D000328:Adult; D001792:Blood Platelets / Q000378:metabolism*; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019007:P-Selectin / Q000032:analysis; D010974:Platelet Aggregation / Q000502:physiology*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*
D016328:NF-kappa B; D019007:P-Selectin; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1
platelet-monocyte aggregates; preeclampsia; sFlt-1