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.
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 messenger RNA is converted to sFlt1-14, whereas endothelial cells 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 endothelial cells 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 messenger RNA editing. sFlt1-14 is the predominant VEGF-inhibiting protein produced by the preeclamptic 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.
Sela
Shay
S
Department of Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Itin
Ahuva
A
Natanson-Yaron
Shira
S
Greenfield
Caryn
C
Goldman-Wohl
Debra
D
Yagel
Simcha
S
Keshet
Eli
E
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D003315:Cornea / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism; D011225:Pre-Eclampsia / Q000097:blood*; D011247:Pregnancy; D020033:Protein Isoforms / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012326:RNA Splicing / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D034421:Sus scrofa; D014327:Trophoblasts / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1