Published online before print May 30, 2008, doi: 10.1161/CIRCRESAHA.108.171504
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Submitted on January 8, 2008
Revised on May 7, 2008
Accepted on May 19, 2008
A Novel Human-Specific Soluble Vascular Endothelial Growth Factor Receptor 1. Cell Type–Specific Splicing and Implications to Vascular Endothelial Growth Factor Homeostasis and Preeclampsia
Shay Sela ;
From the Department of Molecular Biology (S.S., A.I., E.K.), the Hebrew University-Hadassah Medical School; and Department of Obstetrics and Gynecology (S.N.-Y., C.G., D.G.-W., S.Y.), Hadassah University Hospital-Mount Scopus, Jerusalem, Israel.
* To whom correspondence should be addressed. E-mail: keshet{at}cc.huji.ac.il.
A human-specific splicing variant of vascular endothelial growth factor (VEGF) receptor 1 (Flt1) was discovered, producing a soluble receptor (designated sFlt1-14) that is qualitatively different from the previously described soluble receptor (sFlt1) and functioning as a potent VEGF inhibitor. sFlt1-14 is generated in a cell type–specific fashion, primarily in nonendothelial cells. Notably, in vascular smooth muscle cells all Flt1 mRNA is converted to sFlt1-14, whereas ECs of the same human vessel express sFlt1. sFlt1-14 expression by vascular smooth muscle cells is dynamically regulated as evidenced by its upregulation on coculture with ECs or by direct exposure to VEGF. Increased production of soluble VEGF receptors during pregnancy is entirely attributable to induced expression of placental sFlt1-14 starting by the end of the first trimester. Expression is dramatically elevated in the placenta of women with preeclampsia, specifically induced in abnormal clusters of degenerative syncytiotrophoblasts known as syncytial knots, where it may undergo further mRNA editing. sFlt1-14 is the predominant VEGF-inhibiting protein produced by the preeclampsia placenta, accumulates in the circulation, and hence is capable of neutralizing VEGF in distant organs affected in preeclampsia. Together, these findings revealed a new natural VEGF inhibitor that has evolved in humans, possibly to protect nonendothelial cells from adverse VEGF signaling. Furthermore, the study uncovered the identity of a VEGF-blocking protein implicated in preeclampsia.
Key words: VEGF • soluble VEGF receptor • splicing • preeclampsia • vascular smooth muscle cell
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