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A Recently Evolved Novel Trophoblast-Enriched Secreted Form of fms-Like Tyrosine Kinase-1 Variant Is Up-Regulated in Hypoxia and Preeclampsia

Departments of Internal Medicine (C.P.T., N.S.R., E.A.K., K.Z.L.) and Obstetrics and Gynecology (J.I.A.), the Graduate Program in Molecular Biology (C.P.T.), University of Iowa College of Medicine, the Veterans Affairs Medical Center (C.P.T.), Iowa City, Iowa 52242; Department of Comparative Biosciences (T.G.G.), School of Veterinary Medicine, and Department of Obstetrics and Gynecology, School of Medicine and Public Health, and the Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin 53706; and Charité University of Medicine (F.H., R.D.), D-10117 Berlin, Germany

Address all correspondence and requests for reprints to: Christie P. Thomas, Department of Internal Medicine, E300 GH, University of Iowa, 200 Hawkins Drive, Iowa City, Iowa 52242. E-mail: christie-thomas{at}uiowa.edu.

Context: Recent published studies indicate a possible role for sFlt1 in the development of preeclampsia.

Objective: The objective of the study was to investigate the expression and regulation of sFlt1-e15a, a recently described novel C-terminal variant isoform of sFlt1.

Design: The studies included a computational comparative analysis of the genomic locus of sFlt1 across vertebrate species; an assessment of sFlt1 variants in human and rhesus cells and tissues; an analysis of sFlt1 variants transiently expressed in HeLa and COS-7 cells; an evaluation of the effect of hypoxia on sFlt1 expression in trophoblasts; and a comparison of placental sFlt1 expression between pregnancies complicated by preeclampsia and control pregnancies.

Result and Conclusions: sFlt1-e15a emerged as an alternate transcript of Flt1 late in evolution with the insertion of an AluSq sequence into the primate genome after the emergence of the simian infraorder about 40 million years ago. sFlt1-e15a is particularly abundant in human placenta and trophoblasts and is also highly expressed in nonhuman primate placenta. The expressed protein has a C-terminal polyserine tail and, like reference sequence sFlt1 (sFlt1-i13), is glycosylated and secreted. Consistent with a role in placental pathophysiology, hypoxia stimulates sFlt1-e15a expression in isolated cytotrophoblasts and a trophoblast cell line, and differentiation into syncytiotrophoblasts further enhances the effect of hypoxia. Placental levels of sFlt1-e15a and sFlt1-i13 transcripts are significantly elevated in patients with preeclampsia compared with normal pregnancies. We speculate that sFlt1-e15a may contribute to the pathophysiology of preeclampsia.

This article has been cited by other articles:

				J. M. Roberts and A. Rajakumar Preeclampsia and Soluble fms-Like Tyrosine Kinase 1 J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2252 - 2254. [Full Text] [PDF]